bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–08–08
eighty-six papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. Distance to Diagnosing Dermatology Provider as a Predictor of Multiple Melanoma Diagnoses.
  2. NF1-Dependent Transcriptome Regulation in the Melanocyte Lineage and in Melanoma.
  3. Proteomics and Phosphoproteomics Profiling of Drug-Addicted BRAFi-Resistant Melanoma Cells.
  4. Is there an overtreatment of melanoma patients at the end of their life? Results of a multicenter study on 193 melanoma patients.
  5. Clinicopathologic Characteristics and Prognostic Factors Impacting Survival in Melanoma of the Eyelid: Running Title: Prognostic Factors for Survival in Melanoma of the Eyelid.
  6. The Interplay between Nevi and Melanoma Predisposition Unravels Nevi-Related and Nevi-Resistant Familial Melanoma.
  7. Mucosal Melanoma: Pathological Evolution, Pathway Dependency and Targeted Therapy.
  8. Age and Cohort Trends of Malignant Melanoma in the United States.
  9. Naturally occurring Telomerase-specific CD4 T cell Immunity in Melanoma.
  10. Incidence and characteristics of metastatic intracranial lesions in stage III and IV melanoma: a single institute retrospective analysis.
  11. Ipilimumab versus ipilimumab plus anti-PD-1 for metastatic melanoma.
  12. Current Trends of Immunotherapy in the Treatment of Cutaneous Melanoma: A Review.
  13. Prediction of Early Response to Immune Checkpoint Inhibition Using FDG-PET/CT in Melanoma Patients.
  14. Identification of death risk factors of primary melanoma based on the competing risk model.
  15. Loss of Lymphotoxin Alpha-Expressing Memory B Cells Correlates with Metastasis of Human Primary Melanoma.
  16. Stem cell spreading dynamics intrinsically differentiate acral melanomas from nevi.
  17. Defective Natural Killer Cells in Melanoma: Role of NKG2D in Pathogenesis and Immunotherapy.
  18. Distinct Immune Signatures Indicative of Treatment Response and Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy.
  19. MC1R Functions, Expression, and Implications for Targeted Therapy.
  20. Survival analysis following enucleation for uveal melanoma.
  21. Endolysosomal Cation Channels and MITF in Melanocytes and Melanoma.
  22. Proprotein convertase subtilisin/kexin Type 9 is required for Ahnak-mediated metastasis of melanoma into lung epithelial cells.
  23. Surveillance of Sentinel Node-Positive Melanoma Patients Who Receive Adjuvant Therapy Without Undergoing Completion Lymph Node Dissection.
  24. Multidirectional anti-melanoma effect of galactolipids (MGDG-1 and DGDG-1) from Impatiens parviflora DC. and their synergy with doxorubicin.
  25. Development of a Four-mRNA Expression-Based Prognostic Signature for Cutaneous Melanoma.
  26. Gamma-Aminobutyric Acid (GABA) Inhibits α-Melanocyte-Stimulating Hormone-Induced Melanogenesis through GABAA and GABAB Receptors.
  27. Long-Term Maintained Response to Selective Internal Radiation Therapy in an Oligometastatic Uveal Melanoma Patient Treated with Concomitant Anti-PD-1 Therapy.
  28. The AMP-Dependent Kinase Pathway is Upregulated in BAP1 Mutant Uveal Melanoma.
  29. Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma.
  30. Plasma BRAF Mutation Detection for the Diagnostic and Monitoring Trajectory of Patients with LDH-High Stage IV Melanoma.
  31. Melanoma Metastases to the Adrenal Gland Are Highly Resistant to Immune Checkpoint Inhibitors.
  32. Database mining analysis revealed the role of the putative H+/sugar transporter solute carrier family 45 in skin cutaneous melanoma.
  33. Liquid biopsy and radiological response predict outcomes following discontinuation of targeted therapy in patients with BRAF mutated melanoma.
  34. Diffuse PRAME Expression Is Highly Specific for Thin Melanomas in the Distinction from Severely Dysplastic Nevi but Does Not Distinguish Metastasizing from Non-Metastasizing Thin Melanomas.
  35. Nanoliposomes co-encapsulating Ce6 and SB3CT against the proliferation and metastasis of melanoma with the integration of photodynamic therapy and NKG2D-related immunotherapy on A375 cells.
  36. Next-Generation Immunotherapy Approaches in Melanoma.
  37. Distinct Molecular Mechanisms of Altered HLA Class II Expression in Malignant Melanoma.
  38. A375 melanoma cells are sensitized to cisplatin-induced toxicity by a synthetic nitro-flavone derivative 2-(4-Nitrophenyl)-4H-chromen-4-one through inhibition of PARP1.
  39. Enhanced antitumor immune response in melanoma tumor model by anti-PD-1 small interference RNA encapsulated in nanoliposomes.
  40. Aloysia Citrodora Essential Oil Inhibits Melanoma Cell Growth and Migration by Targeting HB-EGF-EGFR Signaling.
  41. ASO Visual Abstract: Cost-Effectiveness Analysis of Adjuvant Therapy for BRAF-Mutant Resected Stage 3 Melanoma in Medicare Patients.
  42. Molecular Mechanisms of Resistance to Immune Checkpoint Inhibitors in Melanoma Treatment: An Update.
  43. TRPV1 and TRPA1 in melanocytes synergize UV-dependent and UV-independent melanogenesis.
  44. Acute granulomatous interstitial nephritis in a patient with metastatic melanoma on targeted therapy with dabrafenib and trametinib-A case report.
  45. ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors.
  46. Anti-Proliferative and Anti-Migratory Activities of Hispidulin on Human Melanoma A2058 Cells.
  47. The evolving role of systemic therapy and local, brain-directed treatment in patients with melanoma and brain metastases.
  48. Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression.
  49. Aggressive Nodular Malignant Melanoma.
  50. Association of Antibiotics and Other Drugs with Clinical Outcomes in Metastatic Melanoma Patients Treated with Immunotherapy.
  51. Bioinformatics analysis of GNAQ, GNA11, BAP1, SF3B1,SRSF2, EIF1AX, PLCB4, and CYSLTR2 genes and their role in the pathogenesis of Uveal Melanoma.
  52. Prediction of Immunotherapy Response in Melanoma through Combined Modeling of Neoantigen Burden and Immune-Related Resistance Mechanisms.
  53. Affinity proteomics and deglycoproteomics uncover novel EDEM2 endogenous substrates and an integrative ERAD network.
  54. Effect of ultraviolet radiation on the Nrf2 signalling pathway in skin cells.
  55. Progressive melanoma vs tumor melanosis: Is imaging enough?
  56. Cloud Computing Based Immunopeptidomics Utilizing Community Curated Variant Libraries Simplifies and Improves Neo-Antigen Discovery in Metastatic Melanoma.
  57. Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2-EphB4 Signaling in Melanoma Metastatic Spine Disease.
  58. Glutamatergic Signaling a Therapeutic Vulnerability in Melanoma.
  59. Definition of Biologically Distinct Groups of Conjunctival Melanomas According to Etiological Factors and Implications for Precision Medicine.
  60. Role of Amine Neurotransmitters and Their Receptors in Skin Pigmentation: Therapeutic Implication.
  61. Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: Systematic review and meta-analysis.
  62. Genome-wide profiles of UV lesion susceptibility, repair, and mutagenic potential in melanoma.
  63. Oral Mucosal Melanoma.
  64. Cold Atmospheric Plasma Changes the Amino Acid Composition of Solutions and Influences the Anti-Tumor Effect on Melanoma Cells.
  65. Impact of age-related T cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: a prospective cohort study.
  66. The impaired UPR-PMEL and TRP channels-autophagy axes in apoptotic melanocytes in vitiligo.
  67. Comparison of two routes of administration of a cationic liposome formulation for a prophylactic DC vaccination in a murine melanoma model.
  68. New Benzimidazothiazolone Derivatives as Tyrosinase Inhibitors with Potential Anti-Melanogenesis and Reactive Oxygen Species Scavenging Activities.
  69. Gender-Dependent Specificities in Cutaneous Melanoma Predisposition, Risk Factors, Somatic Mutations, Prognostic and Predictive Factors: A Systematic Review.
  70. Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy.
  71. Digit melanomas are associated with poor prognostic factors and unfavorable survivals.
  72. 18F-FDG PET/CT versus Diagnostic Contrast-Enhanced CT for Follow-Up of Stage IV Melanoma Patients Treated by Immune Checkpoint Inhibitors: Frequency and Management of Discordances over a 3-Year Period in a University Hospital.
  73. Melanoma of the central nervous system: A report of three cases.
  74. Assessment of Diagnostic Accuracy of Dermoscopic Structures and Patterns Used in Melanoma Detection: A Systematic Review and Meta-analysis.
  75. Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment.
  76. Antiproliferative and antibacterial properties of biocompatible copper(II) complexes bearing chelating N,N-heterocycle ligands and potential mechanisms of action.
  77. Optic Disc Dose Comparison Between 125I and 103Pd Collaborative Ocular Melanoma Study (COMS) Plaques Based on Current Clinical Practice.
  78. NGS Analysis of Liquid Biopsy (LB) and Formalin-Fixed Paraffin-Embedded (FFPE) Melanoma Samples Using Oncomine™ Pan-Cancer Cell-Free Assay.
  79. Systematic Roadmap for Cancer Drug Screening Using Zebrafish Embryo Xenograft Cancer Models: Melanoma Cell Line as a Case Study.
  80. A UVB-responsive common variant at chromosome band 7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor, AHR.
  81. Transcription Factor DLX5 Promotes Hair Follicle Stem Cell Differentiation by Regulating the c-MYC/microRNA-29c-3p/NSD1 Axis.
  82. Confocal microscopy, dermoscopy, and histopathology features of atypical intraepidermal melanocytic proliferations associated with evolution to melanoma in situ.
  83. Behind the Scene: Exploiting MC1R in Skin Cancer Risk and Prevention.
  84. Correction to: Clinical Features, Immunopathogenesis, and Therapeutic Strategies in Vitiligo.
  85. Increased activation of innate immunity and pro-apoptotic CXCR3B in 'normal-appearing' skin on the lesional side of patients with segmental vitiligo.
  86. Arbutin as a Skin Depigmenting Agent with Antimelanogenic and Antioxidant Properties.
  1. J Am Acad Dermatol. 2021 Aug 03. pii: S0190-9622(21)02214-3. [Epub ahead of print]
    Distance to Diagnosing Dermatology Provider as a Predictor of Multiple Melanoma Diagnoses.
    Rose Parisi, John Huppertz, Allison Potolski, Virginia Tracey.
      
    Keywords:  access; dermatology; diagnosis; distance; melanoma; melanoma predictor; patient age
    DOI:  https://doi.org/10.1016/j.jaad.2021.07.051
  2. J Clin Med. 2021 Jul 29. pii: 3350. [Epub ahead of print]10(15):
    NF1-Dependent Transcriptome Regulation in the Melanocyte Lineage and in Melanoma.
    Lionel Larribère, Jochen Utikal.
      The precise role played by the tumor suppressor gene NF1 in melanocyte biology and during the transformation into melanoma is not completely understood. In particular, understanding the interaction during melanocyte development between NF1 and key signaling pathways, which are known to be reactivated in advanced melanoma, is still under investigation. Here, we used RNAseq datasets from either situation to better understand the transcriptomic regulation mediated by an NF1 partial loss of function. We found that NF1 mutations had a differential impact on pluripotency and on melanoblast differentiation. In addition, major signaling pathways such as VEGF, senescence/secretome, endothelin, and cAMP/PKA are likely to be upregulated upon NF1 loss of function in both melanoblasts and metastatic melanoma. In sum, these data bring new light on the transcriptome regulation of the NF1-mutated melanoma subgroup and will help improve the possibilities for specific treatment.
    Keywords:  NF1; RNAseq; melanoblast; melanoma; transcriptome
    DOI:  https://doi.org/10.3390/jcm10153350
  3. J Proteome Res. 2021 Aug 03.
    Proteomics and Phosphoproteomics Profiling of Drug-Addicted BRAFi-Resistant Melanoma Cells.
    Bohui Li, Xiangjun Kong, Harm Post, Linsey Raaijmakers, Daniel S Peeper, Maarten Altelaar.
      Acquired resistance to MAPK inhibitors limits the clinical efficacy in melanoma treatment. We and others have recently shown that BRAF inhibitor (BRAFi)-resistant melanoma cells can develop a dependency on the therapeutic drugs to which they have acquired resistance, creating a vulnerability for these cells that can potentially be exploited in cancer treatment. In drug-addicted melanoma cells, it was shown that this induction of cell death was preceded by a specific ERK2-dependent phenotype switch; however, the underlying molecular mechanisms are largely lacking. To increase the molecular understanding of this drug dependency, we applied a mass spectrometry-based proteomic approach on BRAFi-resistant BRAFMUT 451Lu cells, in which ERK1, ERK2, and JUNB were silenced separately using CRISPR-Cas9. Inactivation of ERK2 and, to a lesser extent, JUNB prevents drug addiction in these melanoma cells, while, conversely, knockout of ERK1 fails to reverse this phenotype, showing a response similar to that of control cells. Our analysis reveals that ERK2 and JUNB share comparable proteome responses dominated by reactivation of cell division. Importantly, we find that EMT activation in drug-addicted melanoma cells upon drug withdrawal is affected by silencing ERK2 but not ERK1. Moreover, transcription factor (regulator) enrichment shows that PIR acts as an effector of ERK2 and phosphoproteome analysis reveals that silencing of ERK2 but not ERK1 leads to amplification of GSK3 kinase activity. Our results depict possible mechanisms of drug addiction in melanoma, which may provide a guide for therapeutic strategies in drug-resistant melanoma.
    Keywords:  BRAF-resistant; EMT; ERK1/MAPK3; ERK2/MAPK1; melanoma; phosphoproteomics; proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.1c00331
  4. J Dtsch Dermatol Ges. 2021 Aug 06.
    Is there an overtreatment of melanoma patients at the end of their life? Results of a multicenter study on 193 melanoma patients.
    Andrea Forschner, Carmen Loquai, Frank Meiss, Svea Huening, Johannes Pawlowski, Fabienne Bradfisch, Saskia Lehr, Dorotheé Nashan.
       BACKGROUND AND OBJECTIVES: There is a lack of data regarding the situation of melanoma patients receiving systemic therapies in their last months of life.
    PATIENTS AND METHODS: All melanoma patients who died in 2016 or 2017 and who had been treated by systemic therapies within the last three months of life were retrospectively analyzed. The study was conducted within the Committee "supportive therapy" of the Work Group Dermatological Oncology (ADO).
    RESULTS: 193 patients from four dermato-oncological centers were included. More than 60 % of the patients had ECOG ≥ 2 and most of them received immune checkpoint inhibitors (ICI) or targeted therapies (TT). 41 patients benefited from the last therapy in terms of radiological and laboratory findings or state of health. Although ECOG was worse in the TT cohort compared to the ICI group, the proportion of patients benefiting from the last therapy with TT was significantly higher and TT therapy could be carried out more often on an outpatient basis.
    CONCLUSIONS: This study indicates that there is a tendency towards an overtreatment at the end of life. Nevertheless, TT might be a reasonable therapeutic option for advanced BRAF mutant melanoma, even in highly palliative situations.
    DOI:  https://doi.org/10.1111/ddg.14501
  5. Am J Ophthalmol. 2021 Jul 31. pii: S0002-9394(21)00397-4. [Epub ahead of print]
    Clinicopathologic Characteristics and Prognostic Factors Impacting Survival in Melanoma of the Eyelid: Running Title: Prognostic Factors for Survival in Melanoma of the Eyelid.
    Cammille C Go, Diana H Kim, Beatrice C Go, Brendan McGeehan, César A Briceño.
       PURPOSE: To examine prognostic factors for survival in patients with melanoma of the eyelid.
    DESIGN: Retrospective cohort analysis SETTING: Population-based study STUDY POPULATION: Patients with primary melanoma of the eyelid diagnosed in the Surveillance, Epidemiology and End Results database between 1975 and 2016.
    MAIN OUTCOMES MEASURES: Survival rates estimated by Kaplan-Meier analysis and mortality hazard ratios(HRs) for overall survival(OS) and disease-specific survival(DSS).
    RESULTS: The cohort consisted of 2257 patients with cutaneous melanoma in the eyelid, representing 1380 cases of melanoma in situ and 877 cases of invasive melanoma. For melanoma in situ and invasive melanoma respectively, at 5-years, the OS rates were 88.6% and 77.1%, while DSS rates were 99.4% and 91.0%. Cox regression analysis for eyelid melanoma indicated that for invasive melanoma, age at diagnosis ≥ 75 years [HR 2.17; 95% confidence interval(CI) (1.02-4.60); p = 0.04], T4 staging (HR 8.45; 95% CI 2.96-25.31; p < 0.001), lymph node involvement (HR 3.61, 95% CI 1.12 - 11.60; p = 0.03), and nodular melanoma (HR 3.31; 95% CI 1.50-7.32; p = 0.003) histological subtype were associated with decreased rates of survival. Sex and tumor ulceration did not impact survival.
    CONCLUSIONS: This study is the largest analysis to date that focuses on DSS for cutaneous melanoma of the eyelid. The most significant predictors for invasive melanoma survival are age 75 years or greater at diagnosis, T4 staging, lymph node involvement, and the nodular melanoma histological subtype. Patients with these attributes are at higher risk and should be counseled regarding prognosis.
    Keywords:  eyelid; melanoma; survival
    DOI:  https://doi.org/10.1016/j.ajo.2021.07.031
  6. Genes (Basel). 2021 Jul 16. pii: 1077. [Epub ahead of print]12(7):
    The Interplay between Nevi and Melanoma Predisposition Unravels Nevi-Related and Nevi-Resistant Familial Melanoma.
    Stefania Pellegrini, Lisa Elefanti, Luigi Dall'Olmo, Chiara Menin.
      Genetic susceptibility to nevi may affect the risk of developing melanoma, since common and atypical nevi are the main host risk factors implicated in the development of cutaneous melanoma. Recent genome-wide studies defined a melanoma polygenic risk score based on variants in genes involved in different pathways, including nevogenesis. Moreover, a predisposition to nevi is a hereditary trait that may account for melanoma clustering in some families characterized by cases with a high nevi density. On the other hand, familial melanoma aggregation may be due to a Mendelian inheritance of high/moderate-penetrance pathogenic variants affecting melanoma risk, regardless of the nevus count. Based on current knowledge, this review analyzes the complex interplay between nevi and melanoma predisposition in a familial context. We review familial melanoma, starting from Whiteman's divergent pathway model to overall melanoma development, distinguishing between nevi-related (cases with a high nevus count and a high polygenic risk score) and nevi-resistant (high/moderate-penetrance variant-carrier cases) familial melanoma. This distinction could better direct future research on genetic factors useful to identify high-risk subjects.
    Keywords:  familial melanoma; nevi; polygenic risk score; risk factors; susceptibility genes
    DOI:  https://doi.org/10.3390/genes12071077
  7. Front Oncol. 2021 ;11 702287
    Mucosal Melanoma: Pathological Evolution, Pathway Dependency and Targeted Therapy.
    Yanni Ma, Ronghui Xia, Xuhui Ma, Robert L Judson-Torres, Hanlin Zeng.
      Mucosal melanoma (MM) is a rare melanoma subtype that originates from melanocytes within sun-protected mucous membranes. Compared with cutaneous melanoma (CM), MM has worse prognosis and lacks effective treatment options. Moreover, the endogenous or exogenous risk factors that influence mucosal melanocyte transformation, as well as the identity of MM precursor lesions, are ambiguous. Consequently, there remains a lack of molecular markers that can be used for early diagnosis, and therefore better management, of MM. In this review, we first summarize the main functions of mucosal melanocytes. Then, using oral mucosal melanoma (OMM) as a model, we discuss the distinct pathologic stages from benign mucosal melanocytes to metastatic MM, mapping the possible evolutionary trajectories that correspond to MM initiation and progression. We highlight key areas of ambiguity during the genetic evolution of MM from its benign lesions, and the resolution of which could aid in the discovery of new biomarkers for MM detection and diagnosis. We outline the key pathways that are altered in MM, including the MAPK pathway, the PI3K/AKT pathway, cell cycle regulation, telomere maintenance, and the RNA maturation process, and discuss targeted therapy strategies for MM currently in use or under investigation.
    Keywords:  melanocytic lesions; mucosal melanocytes; mucosal melanoma; mutations; signaling dependency; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2021.702287
  8. Cancers (Basel). 2021 Jul 31. pii: 3866. [Epub ahead of print]13(15):
    Age and Cohort Trends of Malignant Melanoma in the United States.
    Stephanie G Lashway, Robin B Harris, Leslie V Farland, Mary Kay O'Rourke, Leslie K Dennis.
      The incidence of malignant melanoma in the United States is increasing, possibly due to changes in ultraviolet radiation (UVR) exposure due to lifestyle or increased awareness and diagnosis of melanoma. To determine if more recent birth cohorts experience higher rates of melanoma as they age, we examined age and birth cohort trends in the United States stratified by anatomic site and cancer type (in situ vs. malignant) of the melanoma diagnosed from 1975-2017. Poisson regression of cutaneous melanoma cases per population for 1975-2017 from the Surveillance, Epidemiology, and End Results (SEER) cancer registries was used to estimate age adjusted incidence for five-year birth cohorts restricted to Whites, ages 15-84. The rate of melanoma incidence across birth cohorts varies by anatomic site and sex. Melanomas at all anatomic sites continue to increase, except for head and neck melanomas in men. Much of the increase in malignant melanoma is driven by cases of thin (<1.5 mm) lesions. While increased skin exams may contribute to the increased incidence of in situ and thin melanoma observed across birth cohorts, the shifts in anatomic site of highest melanoma incidence across birth cohorts suggest changes in UVR exposure may also play a role.
    Keywords:  SEER program; epidemiology; melanoma
    DOI:  https://doi.org/10.3390/cancers13153866
  9. J Invest Dermatol. 2021 Aug 02. pii: S0022-202X(21)01667-5. [Epub ahead of print]
    Naturally occurring Telomerase-specific CD4 T cell Immunity in Melanoma.
    Charlée Nardin, Caroline Laheurte, Eve Puzenat, Laura Boullerot, Mélanie Ramseyer, Amélie Marguier, Marion Jacquin, Yann Godet, François Aubin, Olivier Adotevi.
      CD4 T cells play a key role in anticancer immunity. Here, we investigate the clinical relevance of circulating CD4 Th1 response against telomerase (anti-TERT Th1 response) in melanoma patients. The spontaneous anti-TERT Th1 response was detected in 54.5% (85/156) of melanoma patients before treatment. The prevalence of this systemic response was inversely related to Breslow thickness above 1mm and AJCC stage ≥ II (P = 0.001 and 0.032). In contrast to patients treated by targeted therapies, the anti-TERT Th1 immunity was associated with objective response after immune checkpoint inhibitors (ICI) treatment. Hence 86% (18/21) of responder patients exhibited pre-existing anti-TERT Th1 versus 35% (6/19) in non-responders (P = 0.001). This response was also associated with increased progression free survival and overall survival in melanoma patients treated with ICI (P = 0.0008 and 0.012 respectively). Collectively, the presence of circulating anti-TERT Th1 response is inversely related to melanoma evolution and appears to be a predictive factor of response to immunotherapy. Our results highlight the interest of telomerase-specific CD4 Th1 response as a promising blood based biomarker of immune checkpoint inhibitors therapy in melanoma.
    Keywords:  CD4 T cells; Immune checkpoint inhibitor; Melanoma; Telomerase
    DOI:  https://doi.org/10.1016/j.jid.2021.07.160
  10. J Neurooncol. 2021 Aug 05.
    Incidence and characteristics of metastatic intracranial lesions in stage III and IV melanoma: a single institute retrospective analysis.
    Mani Ratnesh S Sandhu, Veronica L Chiang, Thuy Tran, James B Yu, Sarah Weiss, Sarah Goldberg, Mariam Aboian, Harriet M Kluger, Amit Mahajan.
       INTRODUCTION: The study aimed to describe the brain metastases (BM) incidence, at diagnosis and follow-up, in patients initially presenting with stage III or IV melanoma and characterize their metastatic brain lesions. We also sought to describe the association of common genetic mutations and immunotherapy with BM development in advanced melanoma.
    METHODS: Using our institution's tumor registry, we identified patients with initial diagnoses of stage III and stage IV melanoma. In this cohort, we obtained BM incidence at diagnosis and follow-up, characterized the metastatic brain lesions and primary tumor's genetic profile.
    RESULTS: During the follow-up period, 22.9% of patients with an initial diagnosis of stage III developed BM. In this cohort, the median time for BM occurrence was 20 months; [95% CI (14-29)]. Likewise, 37.7% of patients with Stage IV melanoma presented with BM at the time of diagnosis, and 22.7% of remaining patients developed BM at follow-up over a median duration of 6 months [95% CI (4-11)]. Therefore, suggesting an overall incidence of 51.9% in stage IV melanoma. Next, we observed that the incidence of BM development during the follow-up period significantly decreased from 2012 to 2017 (p < 0.001). Lastly, we found a significantly higher frequency of mutational BRAF in the primary tumor of patients with BM (68.7% vs. 31.2%; p = 0.02).
    CONCLUSIONS: While the overall incidence of BM remains high, the decreasing incidence of BM over the follow-up period is promising. Similar BM incidence in patients with an initial diagnosis of stage III or stage IV warrants appropriate imaging surveillance regimen for stage III patients.
    Keywords:  BRAF; Brain metastasis; Imaging surveillance; Melanoma
    DOI:  https://doi.org/10.1007/s11060-021-03813-8
  11. Lancet Oncol. 2021 Aug;pii: S1470-2045(21)00326-0. [Epub ahead of print]22(8): e342
    Ipilimumab versus ipilimumab plus anti-PD-1 for metastatic melanoma.
    Mengqian Li.
      
    DOI:  https://doi.org/10.1016/S1470-2045(21)00326-0
  12. Dermatol Ther (Heidelb). 2021 Aug 02.
    Current Trends of Immunotherapy in the Treatment of Cutaneous Melanoma: A Review.
    Piyu Parth Naik.
      Cutaneous melanoma remains a severe public health threat, with annual incidence increasing slowly but steadily over 4 decades. While early-stage melanomas can typically be treated with complete surgical excision with favorable results, the development of metastatic cancer, which is related to a lower survival rate, is linked to the primary tumor's rising stage and other high-risk features. Even though the first discoveries of an immunological anti-tumor response were published about a century ago, immunotherapy has only been a feasible therapeutic option for cutaneous melanoma in the last 30 years. Nonetheless, for the treatment of various cancers, including metastatic melanoma, the area of cancer immunotherapy has made significant progress in the last decade. As a result, melanoma continues to be the subject of several preclinical and clinical investigations to further understand cancer immunobiology and test different tumor immunotherapies. Immunotherapy's resistance to radiation and cytotoxic chemotherapy is one of its most distinguishing features. Furthermore, the discovery of biomarkers will aid in patient stratification and management during immunotherapy treatment. In this article, we discuss current knowledge and recent developments in immune-mediated therapy of melanoma.
    Keywords:  Immunotherapy; Ipilimumab; Melanoma
    DOI:  https://doi.org/10.1007/s13555-021-00583-z
  13. Cancers (Basel). 2021 Jul 29. pii: 3830. [Epub ahead of print]13(15):
    Prediction of Early Response to Immune Checkpoint Inhibition Using FDG-PET/CT in Melanoma Patients.
    Ken Kudura, Florentia Dimitriou, Lucas Basler, Robert Förster, Daniela Mihic-Probst, Tim Kutzker, Reinhard Dummer, Joanna Mangana, Irene A Burger, Michael C Kreissl.
      We aimed to investigate, whether 18F-2-fluoro-2-desoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans performed at baseline (time point 0; TP 0) and three months after initiation of immunotherapy (time point 1; TP 1) can be used on a metastasis- and patient-level to predict the response to immune-checkpoint inhibition using FDG-PET/CT six months after treatment start (time point 2; TP 2) in metastatic melanoma patients. This single-center retrospective study considered metastatic melanoma patients treated with immune checkpoint inhibition from TP 0 to TP 2. An analysis on a metastasis- and patient-level was carried out. Tumor volume, standardized uptake values SUV (mean, maximum, and peak), metabolic tumor volume MTV and total lesion glycolysis TLG of each included metastasis were recorded at each time point, respectively TP 0, TP 1 and TP 2. Total tumor volume, total metabolic tumor volume and total lesion glycolysis per patient were also calculated at TP 0, TP 1 and TP 2. Treatment response was assessed at metastasis- and patient-level based on FDG-PET/CT scans at TP 2. 612 melanoma metastases in 111 patients were included. The analysis on a metastasis-level showed that metastatic SUVpeak at TP 1 and volume variation between TP 0 and TP 1 were the strongest negative predictive biomarkers for response. However, at TP 0, metastatic SUVmean and SUVpeak indicated a low negative prediction power, whereas initial metastatic volume was not a predictive biomarker. Also, melanoma metastases located in bone structures had a negative influence on the outcome at TP 2, particularly in women. The analysis on a patient-level showed, that total tumor volume, total metastatic tumor volume and total lesion glycolysis of all metastases three months after treatment initiation were strong negative predictive biomarkers for response to immunotherapy six months after initiation. Age and female sex were also found to be negative predictive biomarkers with lower predictive power. Interestingly, total tumor volume at TP 0 and number of metastases at TP 0 as well as the occurrence of early immune-related adverse events between TP 0 and TP 2 did not have any predictive value for early treatment response. FDG-PET/CT performed for treatment response assessment three months after initiation of immune checkpoint inhibition in metastatic melanoma patients can also be used to predict early response to treatment. On a metastasis-level SUV peak and volume variation of metastases are strong outcome predictive biomarkers. On a patient-level total tumor volume and semiquantitative parameters such as total metabolic tumor volume MTV and total lesion glycolysis TLG of all metastases are promising outcome predictive biomarkers. Also, early complete response on a metastasis- and patient-level seems to be predictive for lasting complete response.
    Keywords:  biomarkers; immunotherapy; melanoma; outcome prediction; positron emission tomography computed tomography
    DOI:  https://doi.org/10.3390/cancers13153830
  14. Bull Cancer. 2021 Jul 30. pii: S0007-4551(21)00247-2. [Epub ahead of print]
    Identification of death risk factors of primary melanoma based on the competing risk model.
    Jining Xia, Jing Xiang, Jianguo Fan.
       OBJECTIVE: To preliminarily explore death risk factors in primary melanoma patients.
    METHOD: Competing risk model analysis was used using a large sample public cohort and Cox proportional hazard model was compared.
    RESULT: In the competing risk model analysis, age, gender, ethnicity, stage, site, TMN stage and metastases were the independent risk factors of single primary melanoma (SPM) death. T stage had a particularly important impact on SPM death. T2 stage had a 3.212 times greater risk of interest event than T1 stage [hazard ratio (HR)=3.212, 95%CI: 2.994-3.446], T3 stage was 5.747 times greater than that T1 stage (HR=5.747, 95%CI: 5.337-6.187) and T4 stage had a 7.086 times than T1 stage (HR=7.086, 95%CI: 6.514-7.708). Gender, ethnicity, stage, site, T stage and brain and liver metastases were the independent risk factors of multiple primary melanoma (MPM) death. When some groups had a very high death rate or the reference group had a very low death rate in competing events, the results of Cox proportional hazard model may not be as accurate as the results obtained by fine-Gray regression model.
    CONCLUSION: Early diagnosis and therapy, and prevention of tumor progression and metastases of primary melanoma patients are important measures to improve its prognosis and survival.
    Keywords:  Competing risk model; Primary melanoma; Risk factors for death
    DOI:  https://doi.org/10.1016/j.bulcan.2021.04.020
  15. Diagnostics (Basel). 2021 Jul 12. pii: 1238. [Epub ahead of print]11(7):
    Loss of Lymphotoxin Alpha-Expressing Memory B Cells Correlates with Metastasis of Human Primary Melanoma.
    Franziska Werner, Christine Wagner, Martin Simon, Katharina Glatz, Kirsten D Mertz, Heinz Läubli, Erika Richtig, Johannes Griss, Stephan N Wagner.
      Activated antigen-experienced B cells play an unexpected complex role in anti-tumor immunity in human melanoma patients. However, correlative studies between B cell infiltration and tumor progression are limited by the lack of distinction between functional B cell subtypes. In this study, we examined a series of 59 primary and metastatic human cutaneous melanoma specimens with B cell infiltration. Using seven-color multiplex immunohistochemistry and automated tissue imaging and analysis, we analyzed the spatiotemporal dynamics of three major antigen-experienced B cell subpopulations expressing lymphotoxin alpha (LTA/TNFSF1) or interleukin-10 (IL-10) outside tertiary lymphoid structures. The expression of both LTA and IL-10 was not restricted to a particular B cell subtype. In primary melanomas, these cells were predominantly found at the invasive tumor-stroma front and, in metastatic melanomas, they were also found in the intratumoral stroma. In primary melanomas, decreased densities of LTA+ memory-like and, to a lesser extent, activated B cells were associated with metastasis. Compared with metastatic primary tumors, B cell infiltrates in melanoma metastases were enriched in both LTA+ memory-like and LTA+ activated B cells, but not in any of the IL-10+ B cell subpopulations. Melanoma disease progression shows distinct dynamics of functional B cell subpopulations, with the regulation of LTA+ B cell numbers being more significant than IL-10+ B cell subpopulations.
    Keywords:  Interleukin-10; activated B cells; human melanoma; lymphotoxin alpha; memory B cells; multiplex immunohistochemistry; spatiotemporal dynamics; tumor microenvironment; tumor-associated B cells
    DOI:  https://doi.org/10.3390/diagnostics11071238
  16. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00919-0. [Epub ahead of print]36(5): 109492
    Stem cell spreading dynamics intrinsically differentiate acral melanomas from nevi.
    Sally Eshiba, Takeshi Namiki, Yasuaki Mohri, Tomomi Aida, Naotaka Serizawa, Takakazu Shibata, Hironobu Morinaga, Daisuke Nanba, Yuichi Hiraoka, Kohichi Tanaka, Keiko Miura, Masaru Tanaka, Hisashi Uhara, Hiroo Yokozeki, Toshiaki Saida, Emi K Nishimura.
      Early differential diagnosis between malignant and benign tumors and their underlying intrinsic differences are the most critical issues for life-threatening cancers. To study whether human acral melanomas, deadly cancers that occur on non-hair-bearing skin, have distinct origins that underlie their invasive capability, we develop fate-tracing technologies of melanocyte stem cells in sweat glands (glandular McSCs) and in melanoma models in mice and compare the cellular dynamics with human melanoma. Herein, we report that glandular McSCs self-renew to expand their migratory progeny in response to genotoxic stress and trauma to generate invasive melanomas in mice that mimic human acral melanomas. The analysis of melanocytic lesions in human volar skin reveals that genetically unstable McSCs expand in sweat glands and in the surrounding epidermis in melanomas but not in nevi. The detection of such cell spreading dynamics provides an innovative method for an early differential diagnosis of acral melanomas from nevi.
    Keywords:  acral melanomas; acral nevi; differential diagnosis; eccrine gland; melanocyte stem cell; melanoma model; pigment; risk factor; stem cells; sweat gland
    DOI:  https://doi.org/10.1016/j.celrep.2021.109492
  17. Crit Rev Immunol. 2021 ;41(2): 45-76
    Defective Natural Killer Cells in Melanoma: Role of NKG2D in Pathogenesis and Immunotherapy.
    Roni Touboul, Apostolos Zaravinos, Benjamin Bonavida.
      Melanoma is the most aggressive and deadliest form of skin cancer, and its prognosis is very poor. Although the early detection is responsive to many treatments, metastatic melanoma is refractory to most of them. In the United States, skin melanoma is the fifth most common type of cancer in men and the sixth in women. Current treatment modalities, depending on the cancer stage, consist primarily of surgical excision, chemotherapy, adjuvant therapy, targeted therapies, and immunotherapy. Despite the wide range of therapeutic options and the steadily increasing response rates, a large subset of the treated patients relapse and develop resistance to further treatments. One novel approach in preclinical and clinical trials in immunotherapy is the adaptation of natural killer (NK) cells against resistant cancer cells. NK cells can kill a variety of cancer cell types, as well as the cancer stem cells, while leaving normal cells intact. In skin melanoma, as in most cancers, NK cells in the tumor microenvironment (TME) are functionally impaired. Several factors underlie the defective cause of NK cells, one of which is the dysregulation of the activating receptor NKG2D. This is the dominant receptor in regulating the cytotoxic activity, cytokine production, and regulation of other receptors expressed on NK cells and other lymphocytes. The defective NK cells in cancer models were associated with tumor growth and metastasis. In this review, we discuss the role of NK cells and their phenotypic variants in skin melanoma. Using bioinformatics, we have further analyzed the expression of NKG2D, confirming its low transcript levels in patients with skin melanoma. Furthermore, we show that the CD133 subset of cancer stem cells expresses low levels of NKG2D. Based on these findings we discuss the potential therapeutic approaches that can be exploited to upregulate NKG2D in patients' NK cells and restore their anti-melanoma effects, resulting in tumor regression and prolonged survival.
    DOI:  https://doi.org/10.1615/CritRevImmunol.2021037186
  18. Int J Mol Sci. 2021 Jul 27. pii: 8017. [Epub ahead of print]22(15):
    Distinct Immune Signatures Indicative of Treatment Response and Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy.
    Robin Reschke, Philipp Gussek, Andreas Boldt, Ulrich Sack, Ulrike Köhl, Florian Lordick, Thomas Gora, Markus Kreuz, Kristin Reiche, Jan-Christoph Simon, Mirjana Ziemer, Manfred Kunz.
      To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8+ T cells immediately before treatment (median ± median absolute deviation/MAD 26.7 ± 10.4% vs. 17.2 ± 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3+ T cells before the second cycle of treatment. The percentage of CD8+ effector memory (CD8+CD45RA-CD45RO+CCR7-) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median ± MAD 39.2 ± 7.3% vs. 30.5 ± 4.1% and 37.7 ± 4.6 vs. 24.0 ± 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4+ (CD4+CD38+HLADR+) T cells before the second treatment cycle (median ± MAD 14.9 ± 3.9% vs. 5.3 ± 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs.
    Keywords:  T cells; flow cytometry; immune checkpoint; immunology; melanoma
    DOI:  https://doi.org/10.3390/ijms22158017
  19. J Invest Dermatol. 2021 Aug 04. pii: S0022-202X(21)01441-X. [Epub ahead of print]
    MC1R Functions, Expression, and Implications for Targeted Therapy.
    Stefania Guida, Gabriella Guida, Colin Ronald Goding.
      The G protein-coupled MC1R is expressed in melanocytes and has a pivotal role in human skin pigmentation, with reduced function in human genetic variants exhibiting a red hair phenotype and increased melanoma predisposition. Beyond its role in pigmentation, MC1R is increasingly recognized as promoting UV-induced DNA damage repair. Consequently, there is mounting interest in targeting MC1R for therapeutic benefit. However, whether MC1R expression is restricted to melanocytes or is more widely expressed remains a matter of debate. In this paper, we review MC1R function and highlight that unbiased analysis suggests that its expression is restricted to melanocytes, granulocytes, and the brain.
    DOI:  https://doi.org/10.1016/j.jid.2021.06.018
  20. Eye (Lond). 2021 Aug 02.
    Survival analysis following enucleation for uveal melanoma.
    Guy S Negretti, Sarega Gurudas, Beatrice Gallo, Bertil Damato, Amit K Arora, Sobha Sivaprasad, Mandeep S Sagoo.
       OBJECTIVES: To determine survival outcomes following enucleation for uveal melanoma. To compare these outcomes with the 8th edition AJCC classification and determine the influence of cytogenetics, using Fluorescent in situ Hybridisation (FISH), on survival. To determine whether failure to gain sufficient sample for cytogenetics using Fine Needle Aspiration Biopsy (FNAB) correlates with survival.
    SUBJECTS/METHODS: All patients undergoing primary enucleation for uveal melanoma at Moorfields Eye Hospital between 2012 and 2015 were included. Clinical, pathological, cytological and survival data were analysed for all patients.
    RESULTS: In total, 155 subjects were included. Mean age at enucleation was 65.9 years (SD 14.13). 88 (56.8%) patients died at a mean of three (SD 1.9) years following enucleation. Of these, 52 (33.5%) died from metastatic melanoma, 16 (10.3%) from other causes and 20 (12.9%) causes of death were unknown. Cumulative incidence analysis demonstrated AJCC grade, chromosome 8q gain and monosomy three all predict metastatic mortality. The greatest 5-year mortality rate (62%, SD10.1%) was in those with both chromosome abnormalities and AJCC stage III (Stage IV patients excluded due to low numbers). Largest basal diameter and chromosome status, both independently (p = 0.02 and p < 0.001) predicted metastatic mortality on multivariable regression analysis. Those who had an insufficient sample of cells gained during FNAB (n = 16) had no different prognosis.
    CONCLUSIONS: This study confirms, in this population, the poor survival of patients enucleated for uveal melanomas. It confirms the prognostic utility of adding AJCC grade to cytogenetic information. It demonstrates that the lack of sample in patients undergoing FNAB is not related to prognosis.
    DOI:  https://doi.org/10.1038/s41433-021-01710-y
  21. Biomolecules. 2021 Jul 13. pii: 1021. [Epub ahead of print]11(7):
    Endolysosomal Cation Channels and MITF in Melanocytes and Melanoma.
    Carla Abrahamian, Christian Grimm.
      Microphthalmia-associated transcription factor (MITF) is the principal transcription factor regulating pivotal processes in melanoma cell development, growth, survival, proliferation, differentiation and invasion. In recent years, convincing evidence has been provided attesting key roles of endolysosomal cation channels, specifically TPCs and TRPMLs, in cancer, including breast cancer, glioblastoma, bladder cancer, hepatocellular carcinoma and melanoma. In this review, we provide a gene expression profile of these channels in different types of cancers and decipher their roles, in particular the roles of two-pore channel 2 (TPC2) and TRPML1 in melanocytes and melanoma. We specifically discuss the signaling cascades regulating MITF and the relationship between endolysosomal cation channels, MAPK, canonical Wnt/GSK3 pathways and MITF.
    Keywords:  MCOLN; MITF; TFEB; TPC; TPC1; TPC2; TRPML; TRPML1; calcium; lysosome; mTOR; melanocytes; melanoma; mucolipin; two-pore
    DOI:  https://doi.org/10.3390/biom11071021
  22. Neoplasia. 2021 Aug 02. pii: S1476-5586(21)00062-2. [Epub ahead of print]23(9): 993-1001
    Proprotein convertase subtilisin/kexin Type 9 is required for Ahnak-mediated metastasis of melanoma into lung epithelial cells.
    Jung Min Suh, Yelin Son, Jung-Yeon Yoo, Yookyung Goh, Nabil G Seidah, Sanghyuk Lee, Yun Soo Bae.
      Previously we demonstrated that Ahnak mediates transforming growth factor-β (TGFβ)-induced epithelial-mesenchymal transition (EMT) during tumor metastasis. It is well-known that circulating tumor cells (CTCs) invade the vasculature of adjacent target tissues before working to adapt to the host environments. Currently, the molecular mechanism by which infiltrated tumor cells interact with host cells to survive within target tissue environments is far from clear. Here, we show that Ahnak regulates tumor metastasis through PCSK9 expression. To validate the molecular function of Ahnak in metastasis, B16F10 melanoma cells were injected into WT and Ahnak knockout (Ahnak-/-) mice. Ahnak-/- mice were more resistant to the pulmonary metastasis of B16F10 cells compared to wild-type (WT) mice. To investigate the host function of Ahnak in recipient organs against metastasis of melanoma cells, transcriptomic analyses of primary pulmonary endothelial cells from WT or Ahnak-/- mice in the absence or presence of TGFβ stimulation were performed. We found PCSK9, along with several other candidate genes, was involved in the invasion of melanoma cells into lung tissues. PCSK9 expression in the pulmonary artery was higher in WT mice than Ahnak-/- mice. To evaluate the host function of PCSK9 in lung tissues during the metastasis of melanoma cells, we established lung epithelial cell-specific tamoxifen-induced PCSK9 conditional KO mice (Scgb1a1-Cre/PCSK9fl/fl). The pulmonary metastasis of B16F10 cells in Scgb1a1-Cre/PCSK9fl/fl mice was significantly suppressed, indicating that PCSK9 plays an important role in the metastasis of melanoma cells. Taken together, our data demonstrate that Ahnak regulates metastatic colonization through the regulation of PCSK9 expression.
    Keywords:  Ahnak; Extravasation; Metastasis; PCSK9; TGFβ
    DOI:  https://doi.org/10.1016/j.neo.2021.07.007
  23. Ann Surg Oncol. 2021 Aug 06.
    Surveillance of Sentinel Node-Positive Melanoma Patients Who Receive Adjuvant Therapy Without Undergoing Completion Lymph Node Dissection.
    Kristy K Broman, Deepti Bettampadi, Jaileene Pérez-Morales, James Sun, Dennis Kirichenko, Michael J Carr, Zeynep Eroglu, Ahmad A Tarhini, Nikhil Khushalani, Matthew B Schabath, Amod Sarnaik, Vernon K Sondak, Jonathan S Zager.
       INTRODUCTION: Adjuvant therapy trials required completion lymph node dissection (CLND) for sentinel lymph node (SLN)-positive melanoma prior to systemic treatment, but nodal surveillance without CLND is now common. For patients receiving adjuvant therapy without CLND, patterns of recurrence are unknown and the value of regional nodal ultrasound alongside cross-sectional imaging is not well-defined.
    METHODS: In a retrospective cohort of SLN-positive melanoma patients managed with nodal surveillance from June 2014 to June 2019, we evaluated the association between adjuvant treatment and location of first recurrence (locoregional, nodal, distant, or multisite) using Chi-square tests. We compared methods of recurrence detection and cost by surveillance intensity using Chi-square and Dunn's tests.
    RESULTS: Among 177 nodal surveillance patients, 66 (37%) received adjuvant therapy. Median follow-up was 24 months, during which 48 patients (27%) recurred. Adjuvant treatment did not alter patterns of initial recurrence (p = 0.76). Adjuvant therapy recipients more often had both nodal ultrasound and cross-sectional imaging surveillance (p < 0.01). Among 13 isolated nodal recurrences, 85% were within the first year and 85% were detected by examination and/or ultrasound. Increasing surveillance intensity was not associated with recurrence detection rates but increased overall cost and cost per detected recurrence.
    CONCLUSION: Regardless of adjuvant treatment, most nodal recurrences occurred in the first year and were initially detected clinically or by ultrasound. Findings support continued use of examination and nodal basin ultrasound in addition to any planned cross-sectional imaging surveillance.
    Keywords:  Adjuvant therapy; Lymph node dissection; Melanoma; Sentinel lymph node; Surveillance
    DOI:  https://doi.org/10.1245/s10434-021-10570-5
  24. Toxicol In Vitro. 2021 Aug 03. pii: S0887-2333(21)00156-9. [Epub ahead of print] 105231
    Multidirectional anti-melanoma effect of galactolipids (MGDG-1 and DGDG-1) from Impatiens parviflora DC. and their synergy with doxorubicin.
    Karolina Grabowska, Agnieszka Galanty, Paulina Koczurkiewicz-Adamczyk, Dagmara Wróbel-Biedrawa, Paweł Żmudzki, Daniel Załuski, Katarzyna Wójcik-Pszczoła, Paweł Paśko, Elżbieta Pękala, Irma Podolak.
      The anti-melanoma potential of galactolipids: MGDG-1 and DGDG-1, isolated from Impatiens parviflora, and their synergistic effect with anticancer drug - doxorubicin (DOX) was investigated. Both compounds demonstrated time- and dose-dependent cytotoxicity against human melanoma cells of different metastatic potential. MGDG-1 was more effective than DGDG-1, with the highest activity against A375 cell line (IC50 = 15.14 μg/mL). Both compounds acted selectively, were devoid of hepatotoxicity or mutagenicity. Additionally, MGDG-1 proved to be a tyrosinase inhibitor. Co-administration of MGDG-1 and DGDG-1 with DOX revealed a synergistic cytotoxic effect on melanoma cells. The cytotoxicity of all tested MGDG-1/DOX and DGDG-1/DOX cocktails was considerably higher than that of each agent administered alone. MGDG-1/DOX (Mix3) reduced the viability of A375 melanoma cells almost totally and this effect was 2-fold more potent as compared to DOX alone. Our study indicates that the overall effect is enhanced with the increasing concentration of MGDG-1 in the cocktail. These results open up a possibility for lowering therapeutic doses of chemotherapeutics such as doxorubicin when co-administrated with galactolipids. Thus, MGDG-1 can be prospectively considered as multidirectional anti-melanoma agent and can be recommended for further in vitro and in vivo studies, especially in search for effective combined therapy.
    Keywords:  Anti-melanoma; Anti-tyrosinase; Combined therapy; Digalactosyl diacylglycerol (DGDG); Impatiens; Monogalactosyl diacylglycerol (MGDG)
    DOI:  https://doi.org/10.1016/j.tiv.2021.105231
  25. Front Genet. 2021 ;12 680617
    Development of a Four-mRNA Expression-Based Prognostic Signature for Cutaneous Melanoma.
    Haiya Bai, Youliang Wang, Huimin Liu, Junyang Lu.
      We aim to find a biomarker that can effectively predict the prognosis of patients with cutaneous melanoma (CM). The RNA sequencing data of CM was downloaded from The Cancer Genome Atlas (TCGA) database and randomly divided into training group and test group. Survival statistical analysis and machine-learning approaches were performed on the RNA sequencing data of CM to develop a prognostic signature. Using univariable Cox proportional hazards regression, random survival forest algorithm, and receiver operating characteristic (ROC) in the training group, the four-mRNA signature including CD276, UQCRFS1, HAPLN3, and PIP4P1 was screened out. The four-mRNA signature could divide patients into low-risk and high-risk groups with different survival outcomes (log-rank p < 0.001). The predictive efficacy of the four-mRNA signature was confirmed in the test group, the whole TCGA group, and the independent GSE65904 (log-rank p < 0.05). The independence of the four-mRNA signature in prognostic prediction was demonstrated by multivariate Cox analysis. ROC and timeROC analyses showed that the efficiency of the signature in survival prediction was better than other clinical variables such as melanoma Clark level and tumor stage. This study highlights that the four-mRNA model could be used as a prognostic signature for CM patients with potential clinical application value.
    Keywords:  MRNA expression data; cutaneous melanoma; machine learning; prognostic signature; random survival forest
    DOI:  https://doi.org/10.3389/fgene.2021.680617
  26. Int J Mol Sci. 2021 Jul 31. pii: 8257. [Epub ahead of print]22(15):
    Gamma-Aminobutyric Acid (GABA) Inhibits α-Melanocyte-Stimulating Hormone-Induced Melanogenesis through GABAA and GABAB Receptors.
    Ilandarage Menu Neelaka Molagoda, Mirissa Hewage Dumindu Kavinda, Hyung Won Ryu, Yung Hyun Choi, Jin-Woo Jeong, Sanghyuck Kang, Gi-Young Kim.
      Gamma-aminobutyric acid (GABA) is considered the primary inhibitory neurotransmitter in the human cortex. However, whether GABA regulates melanogenesis has not been comprehensively elucidated. In this study, we reveal that GABA (20 mM) significantly inhibited α-melanocyte-stimulating hormone (α-MSH)-induced extracellular (from 354.9% ± 28.4% to 126.5% ± 16.0%) and intracellular melanin contents (from 236.7% ± 11.1% to 102.7% ± 23.1%) in B16F10 melanoma cells, without inducing cytotoxicity. In addition, α-MSH-induced hyperpigmentation in zebrafish larvae was inhibited from 246.3% ± 5.4% to 116.3% ± 3.1% at 40 mM GABA, displaying no apparent cardiotoxicity. We also clarify that the GABA-mediated antimelanogenic properties were related to the direct inhibition of microphthalmia-associated transcription factor (MITF) and tyrosinase expression by inhibiting cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB). Furthermore, under α-MSH stimulation, GABA-related antimelanogenic effects were mediated through the GABAA and GABAB receptors, with subsequent inhibition of Ca2+ accumulation. In B16F10 melanoma cells and zebrafish larvae, pretreatment with bicuculline, a GABAA receptor antagonist, and CGP 46381, a GABAB receptor antagonist, reversed the antimelanogenic effect of GABA following α-MSH treatment by upregulating Ca2+ accumulation. In conclusion, our results indicate that GABA inhibits α-MSH-induced melanogenesis. Hence, in addition to the health benefits of GABA in the central nervous system, it could ameliorate hyperpigmentation disorders.
    Keywords:  Ca2+; GABA; GABA receptor; melanogenesis
    DOI:  https://doi.org/10.3390/ijms22158257
  27. Life (Basel). 2021 Jul 14. pii: 692. [Epub ahead of print]11(7):
    Long-Term Maintained Response to Selective Internal Radiation Therapy in an Oligometastatic Uveal Melanoma Patient Treated with Concomitant Anti-PD-1 Therapy.
    Ilaria Proietti, Nevena Skroza, Luca Filippi, Nicoletta Bernardini, Alessandra Mambrin, Ersilia Tolino, Giovanni Rossi, Anna Marchesiello, Federica Marraffa, Salvatore Volpe, Oreste Bagni, Concetta Potenza.
      Uveal melanoma (UM) is a primary neoplasm of the eye arising from the melanocytes residing in the iris, ciliary body or choroid. It is the most frequent intraocular malignancy and often determines metastases at distant sites, with a peculiar tropism for the liver. Metastatic UM has a poor prognosis, as any treatment affects the natural course of this fatal disease. Herein, we report a case of a UM metastatic to the liver in a 54 year-old female patient, initially treated with nivolumab without success. The patient was then scheduled for selective internal radiation therapy (SIRT) while continuing immunotherapy. This combination led to a complete and durable response and the patient is currently free of disease, two years after the diagnosis of the hepatic metastases. The association between SIRT and immunotherapy (IT) has very promising perspectives for metastatic UM, especially considering the disappointing or contradictory results of classic chemotherapies, IT alone and targeted therapies. Furthermore, this combination has been shown to have a good security profile. However, further studies are needed to confirm the efficacy of associating SIRT and IT and to clarify some unsolved problems, such as the timing of administration of these two therapies.
    Keywords:  anti-PD1; immunotherapy; selective internal radiation therapy; uveal melanoma
    DOI:  https://doi.org/10.3390/life11070692
  28. Pigment Cell Melanoma Res. 2021 Aug 04.
    The AMP-Dependent Kinase Pathway is Upregulated in BAP1 Mutant Uveal Melanoma.
    Vivian Chua, Anna Han, Nelisa Bechtel, Timothy J Purwin, Emily Hunter, Harbour J William, Andrew E Aplin.
      Metastatic uveal melanoma (UM) responds poorly to targeted therapies and immune checkpoint inhibitors. Loss of BRCA1-associated protein 1 (BAP1) via inactivating mutations in the BAP1 gene is associated with UM progression. Thus, molecular alterations caused by BAP1 dysfunction may be novel therapeutic targets for metastatic UM. Here, we found that phosphorylation of AMP-dependent kinase (AMPK) was elevated in BAP1 altered (or mutant) compared to BAP1 unaltered (or wild-type (WT)) UM tumors. As a readout of AMPK pathway activation, phosphorylation of an AMPK downstream effector, acetyl-CoA-carboxylase (ACC), was also elevated. BAP1 re-expression in BAP1-null UM cell lines decreased phospho-AMPK (pAMPK) and phospho-ACC (pACC) levels. AMPK phosphorylation is mediated by calcium/calmodulin dependent protein kinase kinase 2 (CaMKK2) and potentially liver kinase B1 (LKB1) in BAP1 mutant UM cells. Knockdown of AMPKα1/2 reduced the viability of BAP1 mutant UM cells, indicating a survival function of AMPK in BAP1 mutant UM. Our data suggest that the AMPK pathway is an important mechanism mediating the survival of BAP1 mutant UM. Targeting the AMPK pathway may be a novel therapeutic strategy for metastatic UM.
    Keywords:  AMPK; BAP1; Uveal melanoma; stress
    DOI:  https://doi.org/10.1111/pcmr.13007
  29. Cancers (Basel). 2021 Jul 22. pii: 3676. [Epub ahead of print]13(15):
    Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma.
    Mengshi Li, Dijie Liu, Dongyoul Lee, Yinwen Cheng, Nicholas J Baumhover, Brenna M Marks, Edwin A Sagastume, Zuhair K Ballas, Frances L Johnson, Zachary S Morris, Michael K Schultz.
      Radiotherapy can facilitate the immune recognition of immunologically "cold" tumors and enhance the efficacy of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors (ICIs) in melanoma. Systemic administration of receptor-targeted radionuclide therapy has the potential to selectively deliver radionuclides to multiple tumors throughout the body in metastatic settings. By triggering immunologic cell death and increasing the immune susceptibility of surviving tumor cells in these locations, targeted radionuclide therapies may overcome resistance to ICIs and render immunologically "cold" tumors throughout the body responsive to ICIs and immunologically "hot". Here, we show the anti-tumor cooperation of targeted α-particle radionuclide therapy (α-TRT) and ICIs in preclinical models of melanoma. Melanocortin 1 receptor (MC1R)-targeted radiopeptide [212Pb]VMT01 was employed to deliver α-radiation to melanoma tumors in mice. A single injection of 4.1 MBq [212Pb]VMT01 significantly slowed the tumor growth of B16-F10 melanoma and the combination of [212Pb]VMT01 and ICIs induced a cooperative anti-tumor effect leading to 43% complete tumor response with no sign of malignancy on autopsy. Animals with complete response developed anti-tumor immunity to reject further tumor inoculations. This therapeutic cooperation was completely abolished in RAG1 KO mice, which are deficient in T-cell maturation. In addition, the anti-tumor cooperation was compromised when fractionated [212Pb]VMT01 was used in the combination. We also demonstrated that [212Pb]VMT01 induced immunogenic cell death in tumor vaccination assays and in vitro exposure to [212Pb]VMT01 sensitized immunotolerant melanoma to ICIs treatment in vivo. Enhanced tumor infiltrating CD3+, CD4+, CD8+ lymphocytes were observed following injection of 1.4 MBq [212Pb]VMT01. Overall, we demonstrated anti-tumor cooperation between α-TRT and ICIs in melanoma that is mediated by tumor specific immunity.
    Keywords:  alpha-particle radiotherapy; immune checkpoint inhibitors; immunogenic cell death; immunotherapy; melanoma
    DOI:  https://doi.org/10.3390/cancers13153676
  30. Cancers (Basel). 2021 Aug 03. pii: 3913. [Epub ahead of print]13(15):
    Plasma BRAF Mutation Detection for the Diagnostic and Monitoring Trajectory of Patients with LDH-High Stage IV Melanoma.
    Sofie H Tolmeijer, Rutger H T Koornstra, Jan Willem B de Groot, Maartje J Geerlings, Dirk H van Rens, Marye J Boers-Sonderen, Jack A Schalken, Winald R Gerritsen, Marjolijn J L Ligtenberg, Niven Mehra.
      For patients with newly diagnosed metastatic melanoma, rapid BRAF mutation (mBRAF) assessment is vital to promptly initiate systemic therapy. Additionally, blood-based biomarkers are desired to monitor and predict treatment response. Circulating tumor DNA (ctDNA) has shown great promise for minimally invasive mBRAF assessment and treatment monitoring, but validation studies are needed. This prospective study utilized longitudinal plasma samples at regular timepoints (0, 6, 12, 18 weeks) to address the clinical validity of ctDNA measurements in stage IV melanoma patients with elevated serum lactate dehydrogenase (LDH > 250U/L) starting first-line systemic treatment. Using droplet digital PCR, the plasma mBRAF abundance was assessed in 53 patients with a BRAFV600 tissue mutation. Plasma mBRAF was detected in 50/51 patients at baseline (98% sensitivity; median fraction abundance of 19.5%) and 0/17 controls (100% specificity). Patients in whom plasma mBRAF became undetectable during the first 12-18 weeks of treatment had a longer progression-free survival (30.2 vs. 4.0 months; p < 0.001) and cancer-specific survival (not reached vs. 10.2 months; p < 0.001) compared to patients with detectable mBRAF. The ctDNA dynamics outperformed LDH and S100 dynamics. These results confirm the clinical validity of ctDNA measurements as a minimally invasive biomarker for the diagnostic and monitoring trajectory of patients with LDH-high stage IV melanoma.
    Keywords:  biomarker; circulating tumor DNA (ctDNA), BRAF; lactate dehydrogenase (LDH), S100; melanoma
    DOI:  https://doi.org/10.3390/cancers13153913
  31. J Natl Compr Canc Netw. 2021 Aug 04. pii: jnccn20283. [Epub ahead of print]
    Melanoma Metastases to the Adrenal Gland Are Highly Resistant to Immune Checkpoint Inhibitors.
    Jessica S W Borgers, Richard P Tobin, Robert J Torphy, Victoria M Vorwald, Robert J Van Gulick, Carol M Amato, Dasha T Cogswell, Tugs-Saikhan Chimed, Kasey L Couts, Adrie Van Bokhoven, Christopher D Raeburn, Karl D Lewis, Joshua Wisell, Martin D McCarter, Rao R Mushtaq, William A Robinson.
       BACKGROUND: Adrenal gland metastases (AGMs) are common in advanced-stage melanoma, occurring in up to 50% of patients. The introduction of immune checkpoint inhibitors (ICIs) has markedly altered the outcome of patients with melanoma. However, despite significant successes, anecdotal evidence has suggested that treatment responses in AGMs are significantly lower than in other metastatic sites. We sought to investigate whether having an AGM is associated with altered outcomes and whether ICI responses are dampened in the adrenal glands.
    PATIENTS AND METHODS: We retrospectively compared ICI responses and overall survival (OS) in 68 patients with melanoma who were diagnosed with an AGM and a control group of 100 patients without AGMs at a single institution. Response was determined using RECIST 1.1. OS was calculated from time of ICI initiation, anti-PD-1 initiation, initial melanoma diagnosis, and stage IV disease diagnosis. Tumor-infiltrating immune cells were characterized in 9 resected AGMs using immunohistochemical analysis.
    RESULTS: Response rates of AGMs were significantly lower compared with other metastatic sites in patients with AGMs (16% vs 22%) and compared with those without AGMs (55%). Patients with AGMs also had significantly lower median OS compared with those without AGMs (3.1 years vs not reached, respectively). We further observed that despite this, AGMs exhibited high levels of tumor-infiltrating immune cells.
    CONCLUSIONS: In this cohort of patients with melanoma, those diagnosed with an AGM had lower ICI response rates and OS. These results suggest that tissue-specific microenvironments of AGMs present unique challenges that may require novel, adrenal gland-directed therapies or surgical resection.
    DOI:  https://doi.org/10.6004/jnccn.2020.7800
  32. Channels (Austin). 2021 Dec;15(1): 496-506
    Database mining analysis revealed the role of the putative H+/sugar transporter solute carrier family 45 in skin cutaneous melanoma.
    Jiaheng Xie, Shujie Ruan, Zhechen Zhu, Ming Wang, Yuan Cao, Mengmeng Ou, Pan Yu, Jingping Shi.
      Metabolic reprogramming is common in various cancers. Targeting metabolism to treat tumors is a hot research topic at present. Among them, changes in glucose metabolism in cancer have been widely studied. The Warburg effect maintains a high metabolic level in the tumor, accompanied by changes in glucose transporters. The transmembrane transport of sugar was previously thought to be mediated by SGLT and GLUT. Recently, the Solute Carrier Family(SLC) 45 family may be the third sugar transporter. But the role and value of the SLC45 family in melanoma, a highly malignant skin tumor, is unclear. Our study found that the four members of the SLC45 family, SLC45A1-SLC45A4, were differentially expressed in melanoma, but only SLC45A2 and SLC45A3 had prognostic guiding values. Further analysis revealed that the co-expression patterns of SLC45A2 and SLC45A3 were enriched in multiple metabolic pathways, suggesting their potential role in melanoma. In addition, SLC45A2 and SLC45A3 are also associated with immune cell infiltration. In conclusion, SLC45A2 and SLC45A3 are good prognostic indicators for melanoma and have guiding value for the treatment of melanoma in the future.
    Keywords:  Melanoma; bioinformatics; immunotherapy; solute carrier; transporter
    DOI:  https://doi.org/10.1080/19336950.2021.1956226
  33. Oncologist. 2021 Aug 06.
    Liquid biopsy and radiological response predict outcomes following discontinuation of targeted therapy in patients with BRAF mutated melanoma.
    Lorenza Di Guardo, Giovanni Randon, Francesca Corti, Viviana Vallacchi, Alessandra Raimondi, Giovanni Fucà, Marta Bini, Andrea Maurichi, Roberto Patuzzo, Gianfrancesco Gallino, Ilaria Mattavelli, Roberta Ruggeri, Martina Angi, Mara Cossa, Barbara Valeri, Carolina Cimminiello, Mario Santinami, Licia Rivoltini, Filippo de Braud, Monica Rodolfo, Michele Del Vecchio.
       BACKGROUND: Outcomes of patients with metastatic melanoma discontinuing BRAF-targeted therapy for cumulative toxicity after sustained response are unknown.
    PATIENTS AND METHODS: This retrospective case series analysis conducted at a single Cancer Center in Italy included patients with BRAF mutated metastatic melanoma treated with a BRAF inhibitor as a single agent or in combination with a MEK inhibitor between June 1, 2011 and January 1, 2020 and interrupting treatment after achieving complete response (CR) or long-lasting partial response (PR - i.e. > 12 months) due to cumulative toxicity.
    RESULTS: We included 24 patients with a median treatment duration of 59.4 months (95%CI 55.4-63.4 - range 12-88). CR and PR were achieved in 71% and 29% of patients, respectively. At a median follow-up after treatment discontinuation of 37.8 months (95%CI 33.7-41.9), 12-months progression free survival after discontinuation (dPFS) rate was 70.8% (95%CI 54.8 - 91.6) and 24-months dPFS rate was 58.3% (95%CI 41.6 - 81.8). Baseline patients and tumor characteristics as well as treatment duration and best response did not significantly impact on dPFS. Patients with CR and negative circulating tumor DNA (ctDNA) at time of discontinuation had a significantly improved dPFS compared to patients with either radiological residual disease or ctDNA positivity (P = 0.007). No patient in CR with undetectable ctDNA experienced progression.
    CONCLUSION: The risk of progression is high even in patients with sustained sensitivity to BRAF/MEK inhibitors. Integration of liquid biopsy in clinical trials investigating optimal management of patients with sustained sensitivity to BRAF/MEK inhibitors is warranted.
    IMPLICATIONS FOR PRACTICE: Outcomes of patients with metastatic melanoma discontinuing BRAF-targeted therapy for cumulative toxicity are unknown. We analyzed patients with sustained responses (median treatment duration 59.4 months). Twelve and 24-months progression free survival following discontinuation were 70.8% and 58.3% respectively. Complete response and negative ctDNA at time of discontinuation are promising prognostic biomarkers in this setting.
    DOI:  https://doi.org/10.1002/onco.13926
  34. Cancers (Basel). 2021 Jul 31. pii: 3864. [Epub ahead of print]13(15):
    Diffuse PRAME Expression Is Highly Specific for Thin Melanomas in the Distinction from Severely Dysplastic Nevi but Does Not Distinguish Metastasizing from Non-Metastasizing Thin Melanomas.
    Maximilian Gassenmaier, Matthias Hahn, Gisela Metzler, Jürgen Bauer, Amir Sadegh Yazdi, Ulrike Keim, Claus Garbe, Nikolaus Benjamin Wagner, Stephan Forchhammer.
       BACKGROUND: PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is increasingly used as diagnostic adjunct in the evaluation of melanocytic tumors. The expression and prognostic significance of PRAME in melanomas ≤1.0 mm and its diagnostic utility in the distinction from severely dysplastic compound nevi (SDN) have not been studied.
    METHODS: We investigated and compared the immunohistochemical PRAME expression in 70 matched thin metastasizing and non-metastasizing melanomas and 45 nevi from patients with long-term follow-up (35 SDN and 10 unequivocally benign compound nevi).
    RESULTS: Diffuse PRAME staining in >75% of lesional epidermal and dermal melanocytes identified 58.6% of thin melanomas but did not distinguish metastasizing from non-metastasizing melanomas (p = 0.81). A superficial atypical melanocytic proliferation of uncertain significance, in which the final diagnostic interpretation favored a SDN was the only nevus with diffuse PRAME expression (1/45). Melanomas and SDN with PRAME immunoreactivity exhibited different staining patterns. Most melanomas (67.6%) showed uniform PRAME expression in the in situ and invasive component, whereas most SDN (81.0%) showed a decreasing gradient with depth.
    CONCLUSION: Diffuse intraepidermal and dermal PRAME staining is highly specific for melanomas in the distinction from SDN. PRAME expression is not a prognostic biomarker in melanomas ≤1.0 mm.
    Keywords:  PRAME; dysplastic nevus; histopathology; immunohistochemistry; melanoma; metastasis; nevus; prognosis
    DOI:  https://doi.org/10.3390/cancers13153864
  35. Nanotechnology. 2021 Aug 05.
    Nanoliposomes co-encapsulating Ce6 and SB3CT against the proliferation and metastasis of melanoma with the integration of photodynamic therapy and NKG2D-related immunotherapy on A375 cells.
    Huifang Liu, Cuiping Yao, Luwei Zhang, Jing Xin, Zhenxi Zhang, Sijia Wang.
       PURPOSE: To overcome the insufficiency of conventional photodynamic therapy (PDT) for treating metastatic melanoma, the combination of smart nanoparticles and PDT with immunotherapy was used to achieve a higher efficiency by accumulating more photosensitizers (PSs) in tumor areas and triggering stronger immune responses against tumors after PDT.
    METHODS: In this study, we designed a nanoliposome co-encapsulation of chlorin E6 (Ce6) and SB-3CT to realize significant antitumoral proliferation and metastasis efficacy after laser irradiation in A375 cells. The morphology, size distribution, and loading efficiency of Ce6-SB3CT@Liposome (Lip-SC) were characterized. The reactive oxygen species (ROS) generation and cytotoxicity were evaluated in A375 cells, and the mechanisms of natural killer (NK) cell-mediated killing were assessed.
    RESULTS: Lip-SC showed good stability and was well-dispersed with a diameter of approximately 140 nm in phosphate-buffered saline. The nanoliposomes could accumulate in tumor areas and induce apoptosis in cancer cells upon 660 nm light irradiation, which could trigger an immune response and induce the expression of natural killer group 2 member D (NKG2D) ligands. The subsequently released SB-3CT could further activate NK cells effectively and strengthen the immune system by inhibiting the shedding of soluble NKG2D ligands.
    DISCUSSION: Taken together, the synergistic effects of SB-3CT on nanoliposomes for Ce6-mediated PDT were analyzed in detail to provide a new platform for future anti-melanoma treatment.
    Keywords:  NKG2D ligands; SB-3CT; nanoliposome; photodynamic immunity
    DOI:  https://doi.org/10.1088/1361-6528/ac1afd
  36. Curr Oncol Rep. 2021 Aug 03. 23(10): 116
    Next-Generation Immunotherapy Approaches in Melanoma.
    Tyler Buchanan, Afsaneh Amouzegar, Jason J Luke.
       PURPOSE OF REVIEW: For patients with metastatic melanoma, immune checkpoint inhibition has drastically changed outcomes. Here, we review the current and next generations of immune-based anti-cancer therapeutics for patients with metastatic melanoma.
    RECENT FINDINGS: The need for new anti-cancer therapeutics in patients with metastatic melanoma who have progression of disease despite immune checkpoint blockade is evident. Several novel agents are expected to have FDA approval within the next few years, as they have yielded impressive responses. Despite these optimistic agents, the field of immuno-oncology continues to expand and produce agents with novel mechanisms of action. The next generation of immunotherapy is based upon years of thoroughly researched immuno-oncology. Many of these agents are currently being evaluated in early phase clinical trials, and much of the preliminary data looks promising.
    Keywords:  Cell therapy; Checkpoints; Cytokines; Developmental therapeutics; Immunotherapy; Innate immunity
    DOI:  https://doi.org/10.1007/s11912-021-01104-z
  37. Cancers (Basel). 2021 Aug 03. pii: 3907. [Epub ahead of print]13(15):
    Distinct Molecular Mechanisms of Altered HLA Class II Expression in Malignant Melanoma.
    Stefanie Meyer, Diana Handke, Anja Mueller, Katharina Biehl, Markus Kreuz, Jürgen Bukur, Ulrike Koehl, Maria-Filothei Lazaridou, Mark Berneburg, André Steven, Chiara Massa, Barbara Seliger.
       BACKGROUND: The human leukocyte antigen (HLA) class II molecules are constitutively expressed in some melanoma, but the underlying molecular mechanisms have not yet been characterized.
    METHODS: The expression of HLA class II antigen processing machinery (APM) components was determined in melanoma samples by qPCR, Western blot, flow cytometry and immunohistochemistry. Immunohistochemical and TCGA datasets were used for correlation of HLA class II expression to tumor grading, T-cell infiltration and patients' survival.
    RESULTS: The heterogeneous HLA class II expression in melanoma samples allowed us to characterize four distinct phenotypes. Phenotype I totally lacks constitutive HLA class II surface expression, which is inducible by interferon-gamma (IFN-γ); phenotype II expresses low basal surface HLA class II that is further upregulated by IFN-γ; phenotype III lacks constitutive and IFN-γ controlled HLA class II expression, but could be induced by epigenetic drugs; and in phenotype IV, lack of HLA class II expression is not recovered by any drug tested. High levels of HLA class II APM component expression were associated with an increased intra-tumoral CD4+ T-cell density and increased patients' survival.
    CONCLUSIONS: The heterogeneous basal expression of HLA class II antigens and/or APM components in melanoma cells is caused by distinct molecular mechanisms and has clinical relevance.
    Keywords:  CIITA; HLA class II; IFN; methylation; signal transduction
    DOI:  https://doi.org/10.3390/cancers13153907
  38. Mol Biol Rep. 2021 Aug 03.
    A375 melanoma cells are sensitized to cisplatin-induced toxicity by a synthetic nitro-flavone derivative 2-(4-Nitrophenyl)-4H-chromen-4-one through inhibition of PARP1.
    Anindita Mitra, Rita Ghosh.
       BACKGROUND: Cisplatin has been extensively used in therapeutics for its broad-spectrum anticancer activity and frequently used for the treatment of solid tumors. However, it presents several side-effects and several cancers develop resistance. Combination therapy of cisplatin with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors has been effective in increasing its efficacy at lower doses.
    METHODS AND RESULTS: In this work, we have shown that the nitro-flavone derivative, 2-(4-Nitrophenyl)-4H-chromen-4-one (4NCO), can improve the sensitivity of cancer cells to cisplatin through inhibition of PARP1. The effect of 4NCO on cisplatin toxicity was studied through combination therapy in both exponential and density inhibited A375 melanoma cells. Combination index (CI) was determined from isobologram analysis. The mechanism of cell killing was assessed by lactate dehydrogenase (LDH) assay. Temporal nicotinamide adenine dinucleotide (NAD+) assay was done to show the inhibition of PARP1. We also performed in silico molecular modeling studies to know the binding mode of 4NCO to a modeled PARP1-DNA complex containing cisplatin-crosslinked adduct. The results from both in silico and in cellulo studies confirmed that PARP1 inhibition by 4NCO was most effective in sensitizing A375 melanoma cells to cisplatin. Isobologram analysis revealed that 4NCO reduced cell viability both in exponential and density inhibited A375 cells synergistically. The combination led to cell death through apoptosis.
    CONCLUSION: The synthetic nitro-flavone derivative 4NCO effectively inhibited the important nuclear DNA repair enzyme PARP1 and therefore, could complement the DNA-damaging anticancer drug cisplatin in A375 cells and thus, could act as a potential adjuvant to cisplatin in melanoma therapy.
    Keywords:  Apoptosis; Cisplatin; Combination therapy; Flavone derivative; Molecular Docking; Poly (ADP-ribose) polymerase 1 (PARP1)
    DOI:  https://doi.org/10.1007/s11033-021-06600-w
  39. Cancer Gene Ther. 2021 Aug 02.
    Enhanced antitumor immune response in melanoma tumor model by anti-PD-1 small interference RNA encapsulated in nanoliposomes.
    Mehdi Barati, Farshad Mirzavi, Amin Reza Nikpoor, Mojtaba Sankian, Hasan Namdar Ahmadabad, Anvar Soleimani, Mohammad Mashreghi, Jalil Tavakol Afshar, Mojgan Mohammadi, Mahmoud Reza Jaafari.
      Programmed cell death protein-1 (PD-1), as an immune checkpoint molecule, attenuates T-cell activity and induces T-cell exhaustion. Although siRNA has a great potential in cancer immunotherapy, its delivery to target cells is the main limitation of using siRNA. This study aimed to prepare a liposomal formulation as a siRNA carrier to silence PD-1 expression in T cells and investigate it's in vivo antitumor efficacy. The liposomal siRNA was prepared and characterized by size, zeta potential, and biodistribution. Following that, the uptake assay and mRNA silencing were evaluated in vitro at mRNA and protein levels. siRNA-PD-1 (siPD-1)-loaded liposome nanoparticles were injected into B16F0 tumor-bearing mice to evaluate tumor growth, tumor-infiltrating lymphocytes, and survival rate. Liposomal siPD-1 efficiently silenced PD-1 mRNA expression in T cells (P < 0.0001), and siPD-1-loaded liposomal nanoparticles enhanced the infiltration of T-helper 1 (Th 1) and cytotoxic T lymphocytes into the tumor tissue (P < 0.0001). Liposome-PD-1 siRNA monotherapy and PD-1 siRNA-Doxil (liposomal doxorubicin) combination therapy improved the survival significantly, compared to the control treatment (P < 0.001). Overall, these findings suggest that immunotherapy with siPD-1-loaded liposomes by enhancing T-cell-mediated antitumor immune responses could be considered as a promising strategy for the treatment of melanoma cancer.
    DOI:  https://doi.org/10.1038/s41417-021-00367-9
  40. Int J Mol Sci. 2021 Jul 29. pii: 8151. [Epub ahead of print]22(15):
    Aloysia Citrodora Essential Oil Inhibits Melanoma Cell Growth and Migration by Targeting HB-EGF-EGFR Signaling.
    Yousef Salama, Nidal Jaradat, Koichi Hattori, Beate Heissig.
      Patients diagnosed with melanoma have a poor prognosis due to regional invasion and metastases. The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is found in a subtype of melanoma with a poor prognosis and contributes to drug resistance. Aloysia citrodora essential oil (ALOC-EO) possesses an antitumor effect. Understanding signaling pathways that contribute to the antitumor of ALOC-EO is important to identify novel tumor types that can be targeted by ALOC-EO. Here, we investigated the effects of ALOC-EO on melanoma growth and tumor cell migration. ALOC-EO blocked melanoma growth in vitro and impaired primary tumor cell growth in vivo. Mechanistically, ALOC-EO blocked heparin-binding-epidermal growth factor (HB-EGF)-induced EGFR signaling and suppressed ERK1/2 phosphorylation. Myelosuppressive drugs upregulated HB-EGF and EGFR expression in melanoma cells. Cotreatment of myelosuppressive drugs with ALOC-EO improved the antitumor activity and inhibited the expression of matrix metalloproteinase-7 and -9 and a disintegrin and metalloproteinase domain-containing protein9. In summary, our study demonstrates that ALOC-EO blocks EGFR and ERK1/2 signaling, with preclinical efficacy as a monotherapy or in combination with myelosuppressive drugs in melanoma.
    Keywords:  Aloysia citrodora; EGFR; ERK1/2; HB-EGF; MMP; herb; melanoma; metastasis; plant; proliferation
    DOI:  https://doi.org/10.3390/ijms22158151
  41. Ann Surg Oncol. 2021 Aug 05.
    ASO Visual Abstract: Cost-Effectiveness Analysis of Adjuvant Therapy for BRAF-Mutant Resected Stage 3 Melanoma in Medicare Patients.
    Saam A Mojtahed, Nicole R Boyer, Saieesh A Rao, Thomas F Gajewski, Jennifer Tseng, Kiran K Turaga.
      
    DOI:  https://doi.org/10.1245/s10434-021-10345-y
  42. Biomedicines. 2021 Jul 18. pii: 835. [Epub ahead of print]9(7):
    Molecular Mechanisms of Resistance to Immune Checkpoint Inhibitors in Melanoma Treatment: An Update.
    Sonja Vukadin, Farah Khaznadar, Tomislav Kizivat, Aleksandar Vcev, Martina Smolic.
      Over the past decade, immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced melanoma and ensured significant improvement in overall survival versus chemotherapy. ICI or targeted therapy are now the first line treatment in advanced melanoma, depending on the tumor v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational status. While these new approaches have changed the outcomes for many patients, a significant proportion of them still experience lack of response, known as primary resistance. Mechanisms of primary drug resistance are not fully elucidated. However, many alterations have been found in ICI-resistant melanomas and possibly contribute to that outcome. Furthermore, some tumors which initially responded to ICI treatment ultimately developed mechanisms of acquired resistance and subsequent tumor progression. In this review, we give an overview of tumor primary and acquired resistance mechanisms to ICI and discuss future perspectives with regards to new molecular targets and combinatorial therapies.
    Keywords:  drug resistance; immune check-point inhibitors; immunotherapy; ipilimumab; melanoma; nivolumab; pembrolizumab
    DOI:  https://doi.org/10.3390/biomedicines9070835
  43. Br J Pharmacol. 2021 Aug 06.
    TRPV1 and TRPA1 in melanocytes synergize UV-dependent and UV-independent melanogenesis.
    Qi Jia, Weifeng Tian, Binbin Li, Wen Chen, Wenjie Zhang, Yang Xie, Na Cheng, Qi Chen, Jianru Xiao, Yiwang Zhang, Jian Yang, Shu Wang.
       BACKGROUND AND PURPOSE: Melanogenesis is essential for pigmentation, and deregulated melanogenesis causes pigmentary diseases. PUVA therapy (psoralen plus ultraviolet A, UVA) strongly stimulates pigmentation, but the underlying molecular mechanisms are elusive.
    EXPERIMENTAL APPROACH: Melanin content of cultured human melanocytes was spectrophotometrically measured. Patch-clamp recordings were made in human melanocytes or HEK 293 cells transiently expressing wild type or mutant human TRPV1 and TRPA1 channels. Endogenous expression of TRPV1 and TRPA1 in melanocytes was analyzed by western blotting and was knocked down with siRNA. In vivo pigmentary responses were measured by a colorimeter in mouse ear skin. The expression of TRPV1 and TRPA1 in human pigmented lesions was examined by immunohistochemical staining.
    KEY RESULTS: PUVA strongly stimulated melanogenesis, and PUVA-induced TRPV1 and TRPA1 channel activation in melanocytes and the resulting Ca2+ influx were required for the stimulated melanogenesis both in vitro and in vivo. Agonists-induced TRPV1 and TRPA1 activation alone did not stimulate melanogenesis, but it synergized UVA or intrinsic cAMP and NO signaling pathways to stimulate UV-dependent or UV-independent melanogenesis. Moreover, the expressions of TRPV1 and TRPA1 were increased in human melanocytic lesions, and inhibition of both channels decreased melanin content in melanoma cells.
    CONCLUSION AND IMPLICATIONS: TRPV1 and TRPA1 are key molecular sensors and enhancers of extrinsic and intrinsic melanogenic signals in both physiological and pathological conditions, and activation of both channels in melanocytes contributes to PUVA therapy-induced pigmentation. Our work provides a common mechanism of melanogenic regulation and highlights TRPV1 and TRPA1 as potential therapeutic targets for pigmentary disorders.
    Keywords:  Melanogenesis/Ca2+/TRP channel/PUVA
    DOI:  https://doi.org/10.1111/bph.15643
  44. Cancer Rep (Hoboken). 2021 Aug 05. e1520
    Acute granulomatous interstitial nephritis in a patient with metastatic melanoma on targeted therapy with dabrafenib and trametinib-A case report.
    Anna Krelle, Vinod Kalapurackal Mathai, Geoff Kirkland, Louise Nott, Matthew D Jose, Karen Whale.
       BACKGROUND: Combination molecular targeted therapy with dabrafenib plus trametinib has been shown to improve progression-free survival and overall survival in patients with BRAF V600 mutated unresectable or metastatic melanoma. In general, these agents are well tolerated. Kidney related adverse events are uncommon with only three case reports of acute interstitial nephritis and one case of a serious acute kidney injury. We report another case of interstitial nephritis related to these drugs.
    CASE: A 37-year-old man diagnosed with metastatic melanoma (BRAF V600E mutation) who developed acute interstitial nephritis 5 years into his treatment with combination dabrafenib plus trametinib therapy. He presented with an asymptomatic acute kidney injury on routine surveillance pathology with a creatinine of 174 μmol/L (from baseline 80 μmol/L) and a corresponding estimated glomerular filtration rate (eGFR) of 42 ml/min/1.73 m2 (from a baseline >90 ml/min/1.73 m2 ) and microalbuminuria (albumin creatinine ratio [ACR] 8.5 mg/mmol). Renal biopsy revealed a granulomatous interstitial nephritis likely drug related. He was treated with prednisolone 1 mg/kg and ceased his targeted therapy with improvement in his renal function.
    CONCLUSION: Although rare, recognition of acute interstitial nephritis, a possible serious adverse outcome due to dabrafenib and trametinib is important and needs to be incorporated into current Australian cancer therapy guidelines.
    Keywords:  cancer management; melanoma; targeted therapy
    DOI:  https://doi.org/10.1002/cnr2.1520
  45. Cell Rep Med. 2021 Jul 20. 2(7): 100350
    ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors.
    Ana Portelinha, Scott Thompson, Roger A Smith, Mariana Da Silva Ferreira, Zahra Asgari, Andrea Knezevic, Venkatraman Seshan, Elisa de Stanchina, Sandeep Gupta, Louis Denis, Anas Younes, Sanjeeva Reddy.
      Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAFV600E mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both in vitro and in vivo due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors.
    Keywords:  ASN007; ERK; KRAS; PI3K; RAF/RAS-driven cancers; biomarker; combinational therapy; kinase inhibitor; lymphoma; solid tumors
    DOI:  https://doi.org/10.1016/j.xcrm.2021.100350
  46. Biomolecules. 2021 Jul 16. pii: 1039. [Epub ahead of print]11(7):
    Anti-Proliferative and Anti-Migratory Activities of Hispidulin on Human Melanoma A2058 Cells.
    Chi-Jen Chang, Yen-Ling Hung, Ting-Chen Chen, Hsin-Ju Li, Yuan-Hsin Lo, Nan-Lin Wu, Der-Chen Chang, Chi-Feng Hung.
      Melanoma represents less than 5% of skin cancers, but is the most lethal, mainly because of its high-metastatic potential and resistance to various therapies. Therefore, it is important to develop effective treatments, especially chemotherapeutic drugs with cytotoxicity, anti-metastaticity, and few side effects. One such natural product is hispidulin, a flavone distributed in plants of the Asteraceae. Previous studies have demonstrated that hispidulin has various pharmacological benefits, such as anti-tumor, anti-inflammation, and anti-allergic effects. This study aims to explore the effects of hispidulin against melanoma in vitro and in vivo. Results revealed that hispidulin selectively decreased the cell viability of A2058 cells in a dose- and time-dependent manner. Hispidulin induced cells accumulated in the sub-G1 phase via activating caspase 8 and 9, increased cleaved caspase 3, and cleaved PARP expression. Hispidulin was able to decrease AKT and ERK phosphorylation, which facilitated cell growth and survival. Moreover, hispidulin promoted reactive oxygen species generation in cells and suppressed cell migration through downregulated matrix metalloproteinase-2 expression. Hispidulin significantly inhibited tumor growth in a xenograft model. Based on these results, hispidulin produces its anti-melanoma effects by inducing cancer cell apoptosis and reducing its migration. Therefore, we suggest hispidulin as a potent therapeutic candidate for melanoma treatment.
    Keywords:  hispidulin; melanoma; natural product
    DOI:  https://doi.org/10.3390/biom11071039
  47. Neuro Oncol. 2021 Aug 05. pii: noab194. [Epub ahead of print]
    The evolving role of systemic therapy and local, brain-directed treatment in patients with melanoma and brain metastases.
    Nayan Lamba, Ayal A Aizer.
      
    DOI:  https://doi.org/10.1093/neuonc/noab194
  48. Cancers (Basel). 2021 Jul 25. pii: 3733. [Epub ahead of print]13(15):
    Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression.
    Martina Proctor, Jazmina L Gonzalez Cruz, Sheena M Daignault-Mill, Margaret Veitch, Bijun Zeng, Anna Ehmann, Muhammed Sabdia, Cameron Snell, Colm Keane, Riccardo Dolcetti, Nikolas K Haass, James W Wells, Brian Gabrielli.
      Drugs selectively targeting replication stress have demonstrated significant preclinical activity, but this has not yet translated into an effective clinical treatment. Here we report that targeting increased replication stress with a combination of Checkpoint kinase 1 inhibitor (CHK1i) with a subclinical dose of hydroxyurea targets also promotes pro-inflammatory cytokine/chemokine expression that is independent of cGAS-STING pathway activation and immunogenic cell death in human and murine melanoma cells. In vivo, this drug combination induces tumour regression which is dependent on an adaptive immune response. It increases cytotoxic CD8+ T cell activity, but the major adaptive immune response is a pronounced NKT cell tumour infiltration. Treatment also promotes an immunosuppressive tumour microenvironment through CD4+ Treg and FoxP3+ NKT cells. The number of these accumulated during treatment, the increase in FoxP3+ NKT cells numbers correlates with the decrease in activated NKT cells, suggesting they are a consequence of the conversion of effector to suppressive NKT cells. Whereas tumour infiltrating CD8+ T cell PD-1 and tumour PD-L1 expression was increased with treatment, peripheral CD4+ and CD8+ T cells retained strong anti-tumour activity. Despite increased CD8+ T cell PD-1, combination with anti-PD-1 did not improve response, indicating that immunosuppression from Tregs and FoxP3+ NKT cells are major contributors to the immunosuppressive tumour microenvironment. This demonstrates that therapies targeting replication stress can be well tolerated, not adversely affect immune responses, and trigger an effective anti-tumour immune response.
    Keywords:  CHK1 inhibitor; NKT cells; adaptive immune response; immunogenic cell death; innate immune response; melanoma; replication stress
    DOI:  https://doi.org/10.3390/cancers13153733
  49. Cureus. 2021 Aug;13(8): e16819
    Aggressive Nodular Malignant Melanoma.
    Daniel J Myers, Ethan A Hyde.
      A subtype of malignant melanomas, nodular melanoma often carries a poor prognosis because of local invasion and frequent distant metastasis. Here, we report a case of progressive dyspnea due to one of the largest primary melanomas in the literature to date along with management strategies and elucidate some of the reasons why patients delay seeking care.
    Keywords:  breslow's depth; clark level; malignant; melanoma; nodular
    DOI:  https://doi.org/10.7759/cureus.16819
  50. J Skin Cancer. 2021 ;2021 9120162
    Association of Antibiotics and Other Drugs with Clinical Outcomes in Metastatic Melanoma Patients Treated with Immunotherapy.
    Manish D Angrish, Arun Agha, Rossanna C Pezo.
      Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have improved survival in many advanced cancers including advanced melanoma, renal cell, urothelial, and non-small-cell lung cancers. However, not all patients respond, and immune-related adverse events (irAEs) are common. Commensal gut bacteria may serve as an immunoregulatory link-mediating ICI response and toxicity. Recent studies have shown that a lack of bacterial diversity, known as gut dysbiosis, can have an adverse impact on patients' response to ICIs and predispose to the development of irAEs. Data were collected from 167 patients with metastatic melanoma who received antibiotics within 30 days prior to and/or after initiation of ICI and patients who received NSAIDs, statins, steroids, or proton-pump inhibitors (PPI) within 30 days prior to ICI initiation. The primary outcome was time-to-discontinuation (TTD) of ICI therapy, measured from the date of ICI initiation to the last treatment date. The secondary outcome of interest was toxicity, with incidence of irAEs graded as per the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Here, we demonstrate that individuals who received antibiotics had a significantly shorter time-to-discontinuation (TTD) of the ICI therapy as opposed those who were not administered antibiotics. Consistent with results from previous research, we propose that antibiotics have a negative effect on a patient's response to ICI therapy, most likely due to the result of gut dysbiosis, and should be critically assessed in terms of their use in patients undergoing ICI treatment.
    DOI:  https://doi.org/10.1155/2021/9120162
  51. Ophthalmic Genet. 2021 Aug 06. 1-12
    Bioinformatics analysis of GNAQ, GNA11, BAP1, SF3B1,SRSF2, EIF1AX, PLCB4, and CYSLTR2 genes and their role in the pathogenesis of Uveal Melanoma.
    Dilara Fatma Akin-Bali.
      Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and its metastases are known to be fatal. It is critical to identify molecular markers to be used in potential prognostic evaluation for early diagnosis, treatment, and metastasis or to investigate all aspects of known genetic anomalies. Therefore, this study aimed to analyze the eight genes (GNAQ, GNA11, BAP1, SF3B1, SRSF2, EIF1AX, PLCB4, and CYSLTR2) that are associated with the most common genetic anomalies in UM from a molecular perspective. The genome sequences and expression profiles of 108 UM patients were obtained via bioinformatics tools that provide data from TCGA. The overall mutational load and the mutation patterns for eight genes, in particular, were thoroughly determined. Moreover, PolyPhen2 and SNAP2 tools were used to estimate the oncogenic/pathogenic properties of identified mutations for UM. In addition to the mutation profile, the effects of the presence of a mutation on gene expression and survival were determined. Finally, STRING network analysis was performed to better understand the functional relationships of mutated proteins in cellular processes. There were 27 missense mutations, 16 frameshift mutations, six nonsense mutations, and three splice region mutations among the 52 mutations found in eight genes, and 26 of them had pathogenic properties. BAP1 m-RNA expression was significantly lower in tumors with the mutant genotype (p = .001). The impact of gene expression, which has poor prognostic importance, on survival is statistically significant for high-expressed BAP1 (p = .0015) and low-expressed CYSLTR2 (p = .0021). To assess the current state of this potentially devastating disease, a molecular perspective has been evaluated. Defining this molecular perspective can be useful in developing targeted drug therapies and personalized medicine.
    Keywords:  BAP1; CYSLTR2; Uveal melanoma; gene expression; genetic; mutation
    DOI:  https://doi.org/10.1080/13816810.2021.1961280
  52. Clin Cancer Res. 2021 Aug 01. 27(15): 4265-4276
    Prediction of Immunotherapy Response in Melanoma through Combined Modeling of Neoantigen Burden and Immune-Related Resistance Mechanisms.
    Charles W Abbott, Sean M Boyle, Rachel Marty Pyke, Lee D McDaniel, Eric Levy, Fábio C P Navarro, Dattatreya Mellacheruvu, Simo V Zhang, Mengyao Tan, Rose Santiago, Zeid M Rusan, Pamela Milani, Gabor Bartha, Jason Harris, Rena McClory, Michael P Snyder, Sekwon Jang, Richard Chen.
       PURPOSE: While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB).
    EXPERIMENTAL DESIGN: Tumors from a cohort of patients with late-stage melanoma (n = 51) were profiled using an immune-enhanced exome and transcriptome platform. We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB.
    RESULTS: Our neoantigen burden score, which integrates both exome and transcriptome features, more significantly stratified responders and nonresponders (P = 0.016) than TMB alone (P = 0.049). Extension of this model to include immune-related resistance mechanisms affecting the antigen presentation machinery, such as HLA allele-specific LOH, resulted in a composite neoantigen presentation score (NEOPS) that demonstrated further increased association with therapy response (P = 0.002).
    CONCLUSIONS: NEOPS proved the statistically strongest biomarker compared with all single-gene biomarkers, expression signatures, and TMB biomarkers evaluated in this cohort. Subsequent confirmation of these findings in an independent cohort of patients (n = 110) suggests that NEOPS is a robust, novel biomarker of ICB response in melanoma.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-4314
  53. Mol Cell Proteomics. 2021 Jul 28. pii: S1535-9476(21)00097-9. [Epub ahead of print] 100125
    Affinity proteomics and deglycoproteomics uncover novel EDEM2 endogenous substrates and an integrative ERAD network.
    Cristian V A Munteanu, Gabriela N Chirițoiu, Marioara Chirițoiu, Simona Ghenea, Andrei-Jose Petrescu, Ștefana M Petrescu.
      Various pathologies result from disruptions to or stress of endoplasmic reticulum (ER) homeostasis, such as Parkinson's disease and most neurodegenerative illnesses, diabetes, pulmonary fibrosis, viral infections and cancers. A critical process in maintaining ER homeostasis is the selection of misfolded proteins by the ER quality-control system (ERQC) for destruction via ER-associated degradation (ERAD). One key protein proposed to act during the first steps of misfolded glycoprotein degradation is the ER degradation-enhancing α-mannosidase-like protein 2 (EDEM2). Therefore, characterization of the EDEM2 associated proteome is of great interest. We took advantage of using melanoma cells overexpressing EDEM2 as a cancer model system, to start documenting at the deglycoproteome level (N-glycosites identification) the emerging link between ER homeostasis and cancer progression. The dataset created for identifying the EDEM2 glyco-clients carrying high mannose/hybrid N-glycans provides a comprehensive N-glycosites analysis mapping over 1000 N-glycosites on more than 600 melanoma glycoproteins. To identify EDEM2-associated proteins we used affinity-proteomics and proteome-wide analysis of sucrose density fractionation in an integrative workflow. Using intensity and spectral count-based quantification, we identify seven new EDEM2 partners, all of which are involved in ERQC and ERAD. Moreover, we defined novel endogenous candidates for EDEM2-dependent ERAD by combining deglycoproteomics, SILAC-based proteomics, and biochemical methods. These included tumor antigens and several ER-transiting endogenous melanoma proteins, including ITGA1 and PCDH2, the expression of which was negatively correlated with that of EDEM2. Tumor antigens are key in the antigen presentation process, whilst ITGA1 and PCDH2 are involved in melanoma metastasis and invasion. EDEM2 could therefore have a regulatory role in melanoma through the modulation of these glycoproteins degradation and trafficking. The data presented herein suggest that EDEM2 is involved in ER homeostasis to a greater extent than previously suggested.
    Keywords:  EDEM2; ER quality control; ERAD; glycoproteomics; mass spectrometry; melanoma; proteomics; pulse-SILAC
    DOI:  https://doi.org/10.1016/j.mcpro.2021.100125
  54. Int J Radiat Biol. 2021 Jul 31. 1-48
    Effect of ultraviolet radiation on the Nrf2 signalling pathway in skin cells.
    Alena Ryšavá, Jitka Vostálová, Alena Rajnochová Svobodová.
       PURPOSE: Excessive exposure of skin to solar radiation is associated with greatly increased production of reactive oxygen and nitrogen species (ROS, RNS) resulting in oxidative stress (OS), inflammation, immunosuppression, the production of matrix-metalloproteases, DNA damage and mutations. These events lead to increased incidence of various skin disorders including photoageing and both non-melanoma and melanoma skin cancers. The ultraviolet (UV) part of sunlight, in particular, is responsible for structural and cellular changes across the different layers of the skin. Among other effects, UV photons stimulate oxidative damage to biomolecules via the generation of unstable and highly reactive compounds. In response to oxidative damage, cytoprotective pathways are triggered. One of these is the pathway driven by the nuclear factor erythroid-2 related factor 2 (Nrf2). This transcription factor translocates to the nucleus and drives the expression of numerous genes, among them various detoxifying and antioxidant enzymes. Several studies concerning the effects of UV radiation on Nrf2 activation have been published, but different UV wavelengths, skin cells or tissues and incubation periods were used in the experiments that complicate the evaluation of UV radiation effects.
    CONCLUSIONS: This review summarizes the effects of UVB (280-315 nm) and UVA (315-400 nm) radiation on the Nrf2 signalling pathway in dermal fibroblasts and epidermal keratinocytes and melanocytes. The effects of natural compounds (pure compounds or mixtures) on Nrf2 activity and level as well as on Nrf2-driven genes in UV irradiated human skin fibroblasts, keratinocytes and melanocytes are briefly mentioned as well.HighlightsUVB radiation is a rather poor activator of the Nrf2-driven pathway in fibroblastsUVA radiation stimulates Nrf2 activation in dermal fibroblastsEffects of UVA on the Nrf2 pathway in keratinocytes and melanocytes remain unclearLong-term Nrf2 activation in keratinocytes disturbs their normal differentiationPharmacological activation of Nrf2 in skin needs to be performed carefully.
    Keywords:  Nrf2; UV radiation; oxidative stress; photoprotection; phytochemicals; skin
    DOI:  https://doi.org/10.1080/09553002.2021.1962566
  55. Ann Oncol. 2021 Aug 02. pii: S0923-7534(21)02212-2. [Epub ahead of print]
    Progressive melanoma vs tumor melanosis: Is imaging enough?
    T M Davidson, S N Markovic, M S Block, R Guo.
      
    DOI:  https://doi.org/10.1016/j.annonc.2021.07.014
  56. Cancers (Basel). 2021 Jul 26. pii: 3754. [Epub ahead of print]13(15):
    Cloud Computing Based Immunopeptidomics Utilizing Community Curated Variant Libraries Simplifies and Improves Neo-Antigen Discovery in Metastatic Melanoma.
    Amol Prakash, Keira E Mahoney, Benjamin C Orsburn.
      Unique peptide neo-antigens presented on the cell surface are attractive targets for researchers in nearly all areas of personalized medicine. Cells presenting peptides with mutated or other non-canonical sequences can be utilized for both targeted therapies and diagnostics. Today's state-of-the-art pipelines utilize complementary proteogenomic approaches where RNA or ribosomal sequencing data helps to create libraries from which tandem mass spectrometry data can be compared. In this study, we present an alternative approach whereby cloud computing is utilized to power neo-antigen searches against community curated databases containing more than 7 million human sequence variants. Using these expansive databases of high-quality sequences as a reference, we reanalyze the original data from two previously reported studies to identify neo-antigen targets in metastatic melanoma. Using our approach, we identify 79 percent of the non-canonical peptides reported by previous genomic analyses of these files. Furthermore, we report 18-fold more non-canonical peptides than previously reported. The novel neo-antigens we report herein can be corroborated by secondary analyses such as high predicted binding affinity, when analyzed by well-established tools such as NetMHC. Finally, we report 738 non-canonical peptides shared by at least five patient samples, and 3258 shared across the two studies. This illustrates the depth of data that is present, but typically missed by lower statistical power proteogenomic approaches. This large list of shared peptides across the two studies, their annotation, non-canonical origin, as well as MS/MS spectra from the two studies are made available on a web portal for community analysis.
    Keywords:  cloud computing; immunopeptidomics; neoantigen; non-canonical
    DOI:  https://doi.org/10.3390/cancers13153754
  57. Int J Mol Sci. 2021 Jul 27. pii: 8028. [Epub ahead of print]22(15):
    Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2-EphB4 Signaling in Melanoma Metastatic Spine Disease.
    Andras Piffko, Thomas Broggini, Christoph Harms, Ralf Heinrich Adams, Peter Vajkoczy, Marcus Czabanka.
      Tumor-endothelial cell interactions represent an essential mechanism in spinal metastasis. Ephrin-B2-EphB4 communication induces tumor cell repulsion from the endothelium in metastatic melanoma, reducing spinal bone metastasis formation. To shed further light on the Ephrin-B2-EphB4 signaling mechanism, we researched the effects of pharmacological EphB4 receptor stimulation and inhibition in a ligand-dependent/independent context. We chose a preventative and a post-diagnostic therapeutic window. EphB4 stimulation during tumor cell seeding led to an increase in spinal metastatic loci and number of disseminated melanoma cells, as well as earlier locomotion deficits in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, reduction of metastatic loci with a later manifestation of locomotion deficits occurred. Thus, EphB4 receptor stimulation affects metastatic dissemination depending on the presence/absence of endothelial Ephrin-B2. After the manifestation of solid metastasis, EphB4 kinase inhibition resulted in significantly earlier manifestation of locomotion deficits in the presence of the ligand. No post-diagnostic treatment effect was found in the absence of endothelial Ephrin-B2. For solid metastasis treatment, EphB4 kinase inhibition induced prometastatic effects in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, both therapies showed no effect on the growth of solid metastasis.
    Keywords:  Ephrin-B2–EphB4; cancer therapy; seed and soil; spinal bone metastasis
    DOI:  https://doi.org/10.3390/ijms22158028
  58. Cancers (Basel). 2021 Jul 31. pii: 3874. [Epub ahead of print]13(15):
    Glutamatergic Signaling a Therapeutic Vulnerability in Melanoma.
    Kevinn Eddy, Suzie Chen.
      Like other cancers, melanomas are associated with the hyperactivation of two major cell signaling cascades, the MAPK and PI3K/AKT pathways. Both pathways are activated by numerous genes implicated in the development and progression of melanomas such as mutated BRAF, RAS, and NF1. Our lab was the first to identify yet another driver of melanoma, Metabotropic Glutamate Receptor 1 (protein: mGluR1, mouse gene: Grm1, human gene: GRM1), upstream of the MAPK and PI3K/AKT pathways. Binding of glutamate, the natural ligand of mGluR1, activates MAPK and PI3K/AKT pathways and sets in motion the deregulated cellular responses in cell growth, cell survival, and cell metastasis. In this review, we will assess the proposed modes of action that mediate the oncogenic properties of mGluR1 in melanoma and possible application of anti-glutamatergic signaling modulator(s) as therapeutic strategy for the treatment of melanomas.
    Keywords:  MAPK; Metabotropic Glutamate Receptor; PI3K/AKT; anti-glutamatergic signaling inhibitor; cancer mouse models; glutamate; glutamatergic signaling; melanoma; therapeutic targeting
    DOI:  https://doi.org/10.3390/cancers13153874
  59. Cancers (Basel). 2021 Jul 30. pii: 3836. [Epub ahead of print]13(15):
    Definition of Biologically Distinct Groups of Conjunctival Melanomas According to Etiological Factors and Implications for Precision Medicine.
    Sophie Gardrat, Alexandre Houy, Kelly Brooks, Nathalie Cassoux, Raymond Barnhill, Stéphane Dayot, Ivan Bièche, Virginie Raynal, Sylvain Baulande, Richard Marais, Sergio Roman-Roman, Marc-Henri Stern, Manuel Rodrigues.
      Conjunctival melanoma (ConjMel) is a potentially deadly ocular melanoma, originating from partially sunlight-exposed mucosa. We explored the mutational landscape of ConjMel and studied the correlation with etiological factors. We collected 47 primary ConjMel samples and performed next-generation sequencing of 400 genes. Hotspot mutations in BRAF, NRAS, HRAS, and KIT were observed in 16 (34%), 5 (11%), 2, and 2 cases, respectively. Patients with BRAF and CDKN2A-mutated ConjMel tended to be younger while the NF1-mutated one tended to be older. The eight tumors arising from nevi were enriched in CTNNB1 mutations (63% vs. 8%; Fisher's exact p-test = 0.001) compared to non-nevi ConjMel and five were devoid of BRAF, RAS, NF1, or KIT mutations, suggesting a specific oncogenic process in these tumors. The two KIT-mutated cases carried SF3B1 mutations and were located on sun-protected mucosa, a genotype shared with genital and anorectal mucosal melanomas. Targetable mutations were observed in ERBB2, IDH1, MET, and MAP2K1 (one occurrence each). Mutational landscape of ConjMel characterizes distinct molecular subtypes with oncogenic drivers common with mucosal and skin melanomas. CTNNB1 mutations were associated with nevus-derived ConjMel. Concomitant KIT/SF3B1 mutations in sun-protected cases suggest a common tumorigenic process with genital and anorectal mucosal melanomas.
    Keywords:  BRAF; CTNNB1; KIT; NRAS; conjunctival melanoma; nevus; primary acquired melanocytosis; sun exposure
    DOI:  https://doi.org/10.3390/cancers13153836
  60. Int J Mol Sci. 2021 Jul 28. pii: 8071. [Epub ahead of print]22(15):
    Role of Amine Neurotransmitters and Their Receptors in Skin Pigmentation: Therapeutic Implication.
    Enkhmend Enkhtaivan, Chang Hoon Lee.
      Skin pigmentation can occur due to increased melanin, including melanocyte proliferation, melanin biosynthesis, or melanocyte migration. There are many factors that influence the melanin production process, but the role of neurotransmitters in this process is still unclear. We found that histamine and serotonin influence the different stages of melanogenesis and melanogenesis, which increase melanogenesis. Since then, several related papers have been published, and from these papers, it has been recognised that the role of neurotransmitters in skin-pigment-related diseases needs to be summarised. By introducing the role of neurotransmitters in the regulation of various pigment disorders, including vitiligo and melasma, through this review, many researchers can be expected to try to apply neurotransmitter-related agonists and antagonists as treatments for skin pigment disorders.
    Keywords:  acetylcholine; dopamine; histamime; melanogenesis; serotonin; skin pigment abnormality; vitiligo
    DOI:  https://doi.org/10.3390/ijms22158071
  61. PLoS One. 2021 ;16(8): e0255716
    Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: Systematic review and meta-analysis.
    Náthali Felícia Mineiro Dos Santos Garrett, Ana Cristina Carvalho da Costa, Elaine Barros Ferreira, Giovanni Damiani, Paula Elaine Diniz Dos Reis, Christiane Inocêncio Vasques.
       BACKGROUND: Checkpoint inhibitors have revolutionized advanced melanoma care; however, their cutaneous side effects have not been definitively elucidated.
    OBJECTIVE: To identify the prevalence of cutaneous toxicity in patients with melanoma treated with immune checkpoint inhibitors as monotherapy and/or in combination with chemotherapy and/or radiotherapy.
    MATERIALS AND METHODS: We performed a systematic review and meta-analysis, which encompassed both clinical trials and observational studies describing the dermatological toxicities in patients treated with immune checkpoint inhibitors. The protocol was registered in the International Prospective Register of Systematic Review under the number CRD42018091915. The searches were performed using the CINAHL, Cochrane CENTRAL, LILACS, LIVIVO, PubMed, Scopus, and Web of Science databases. The methodological quality of the studies was evaluated with the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data.
    RESULTS: A total of 9,802 articles were identified in the databases. The final sample comprised 39 studies. The evaluated drugs were ipilimumab, tremelimumab, pembrolizumab, and nivolumab. The results suggest that the most prevalent side effect was grade 1 and 2 pruritus (24%), followed by grade 1 and 2 rash (21%) and grade 1 and 2 vitiligo (10%).
    CONCLUSION: The most prevalent side effects in patients treated with checkpoint inhibitors are pruritus, rash, and vitiligo, and they are rated mostly as grades 1 and 2 adverse events. Remarkably, vitiligo is most commonly found in patients treated with PD-1 inhibitors.
    DOI:  https://doi.org/10.1371/journal.pone.0255716
  62. Mutat Res. 2021 Jul 17. pii: S0027-5107(21)00021-X. [Epub ahead of print]823 111758
    Genome-wide profiles of UV lesion susceptibility, repair, and mutagenic potential in melanoma.
    Brian S Perez, Ka Man Wong, Erin K Schwartz, Rafael E Herrera, Devin A King, Pablo E García-Nieto, Ashby J Morrison.
      Exposure to the ultraviolet (UV) radiation in sunlight creates DNA lesions, which if left unrepaired can induce mutations and contribute to skin cancer. The two most common UV-induced DNA lesions are the cis-syn cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), both of which can initiate mutations. Interestingly, mutation frequency across the genomes of many cancers is heterogenous with significant increases in heterochromatin. Corresponding increases in UV lesion susceptibility and decreases in repair are observed in heterochromatin versus euchromatin. However, the individual contributions of CPDs and 6-4PPs to mutagenesis have not been systematically examined in specific genomic and epigenomic contexts. In this study, we compared genome-wide maps of 6-4PP and CPD lesion abundances in primary cells and conducted comprehensive analyses to determine the genetic and epigenetic features associated with susceptibility. Overall, we found a high degree of similarity between 6-4PP and CPD formation, with an enrichment of both in heterochromatin regions. However, when examining the relative levels of the two UV lesions, we found that bivalent and Polycomb-repressed chromatin states were uniquely more susceptible to 6-4PPs. Interestingly, when comparing UV susceptibility and repair with melanoma mutation frequency in these regions, disparate patterns were observed in that susceptibility was not always inversely associated with repair and mutation frequency. Functional enrichment analysis hint at mechanisms of negative selection for these regions that are essential for cell viability, immune function and induce cell death when mutated. Ultimately, these results reveal both the similarities and differences between UV-induced lesions that contribute to melanoma.
    Keywords:  6-4PP; CPD; Excision repair; Melanoma; UV susceptibility; UV-induced mutations
    DOI:  https://doi.org/10.1016/j.mrfmmm.2021.111758
  63. J Craniofac Surg. 2021 Jul 30.
    Oral Mucosal Melanoma.
    Marco Nisi, Rossana Izzetti, Stefano Gennai, Angela Pucci, Chiara Lenzi, Filippo Graziani.
      
    DOI:  https://doi.org/10.1097/SCS.0000000000008054
  64. Int J Mol Sci. 2021 Jul 23. pii: 7886. [Epub ahead of print]22(15):
    Cold Atmospheric Plasma Changes the Amino Acid Composition of Solutions and Influences the Anti-Tumor Effect on Melanoma Cells.
    Stephanie Arndt, Fadi Fadil, Katja Dettmer, Petra Unger, Marko Boskovic, Claudia Samol, Anja-Katrin Bosserhoff, Julia L Zimmermann, Michael Gruber, Wolfram Gronwald, Sigrid Karrer.
      Cold Atmospheric Plasma (CAP) is an ionized gas near room temperature. Its anti-tumor effect can be transmitted either by direct treatment or mediated by a plasma-treated solution (PTS), such as treated standard cell culture medium, which contains different amino acids, inorganic salts, vitamins and other substances. Despite extensive research, the active components in PTS and its molecular or cellular mechanisms are not yet fully understood. The purpose of this study was the measurement of the reactive species in PTS and their effect on tumor cells using different plasma modes and treatment durations. The PTS analysis yielded mode- and dose-dependent differences in the production of reactive oxygen and nitrogen species (RONS), and in the decomposition and modification of the amino acids Tyrosine (Tyr) and Tryptophan (Trp). The Trp metabolites Formylkynurenine (FKyn) and Kynurenine (Kyn) were produced in PTS with the 4 kHz (oxygen) mode, inducing apoptosis in Mel Im melanoma cells. Nitrated derivatives of Trp and Tyr were formed in the 8 kHz (nitrogen) mode, elevating the p16 mRNA expression and senescence-associated ß-Galactosidase staining. In conclusion, the plasma mode has a strong impact on the composition of the active components in PTS and affects its anti-tumor mechanism. These findings are of decisive importance for the development of plasma devices and the effectiveness of tumor treatment.
    Keywords:  amino acid; anti-tumor; apoptosis; cold atmospheric plasma (CAP); melanoma; plasma-treated solution (PTS); senescence
    DOI:  https://doi.org/10.3390/ijms22157886
  65. Aging Cancer. 2020 Dec;1(1-4): 58-70
    Impact of age-related T cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: a prospective cohort study.
    Jason E Galloway, Andrea M Holderbaum, Namrata Arya, Suohui Zhang, Michael S Bodnar, Ruthann Norman, William E Carson, Lianbo Yu, Kari L Kendra, Christin E Burd.
       Background: The impact of biologic aging on immune checkpoint inhibitor (ICI) toxicity and efficacy is underexplored in metastatic melanoma (MM). In peripheral blood T-lymphocytes (PBTLs), biologic aging is characterized by changes in T-cell composition and cellular senescence. Whether indicators of PBTL biologic aging vary in MM patients or can be used to predict premature ICI discontinuation (pID) is unknown.
    Methods: We prospectively collected PBTLs from 117 cancer-free controls and 46 MM patients scheduled to begin pembrolizumab or nivolumab monotherapy. 74 mRNAs indicative of T-cell subsets, activation, co-stimuation/inhibition and cellular senescence were measured by Nanostring. Relationships between each mRNA and chronologic age were assessed in patients and controls. Candidate biomarkers were identified by calculating the hazard ratio (HR) for pID in patients divided into low and high groups based on log-transformed mRNA levels or the magnitude by which each mRNA measurement deviated from the control trend (Δage). Area under the curve (AUC) analyses explored the ability of each biomarker to discriminate between patients with and without pID at 6 months and 1 year.
    Results: Fifteen mRNAs correlated with chronologic age in controls, including markers of T-cell subsets, differentiation, cytokine production and co-stimulation/inhibition. None of these mRNAs remained correlated with age in patients. Median follow-up was 94.8 (1.6-195.7) weeks and 35 of 46 patients discontinued therapy (23 progression, 7 toxicity, 5 comorbidity/patient preference). Elevated pre-therapy CD8A (HR 2.2[1.1-4.9]), CD45RB (HR 2.9[1.4-5.8]) and TNFRSF14 (HR 2.2[1.1-4.5]) levels predicted pID independent of Δage-correction. CD3ε, CD27 and FOXO1 predicted pID only after Δage-correction (HR 2.5[1.3-5.1]; 3.7[1.8-7.8]; 2.1[1.1-4.3]). AUC analysis identified Δage-CD3ε and -CD27 as candidate predictors of pID (AUC=0.73; 0.75).
    Conclusions: Correlations between transcriptional markers of PBTL composition and chronologic age are disrupted in MM. Correcting for normal, age-related trends in biomarker expression unveils new biomarker candidates predictive of ICI outcomes.
    Keywords:  Aging biomarker; CD27; T cell; aging; anti-PD-1; biomarker; checkpoint inhibitor; melanoma; senescence
    DOI:  https://doi.org/10.1002/aac2.12012
  66. Pigment Cell Melanoma Res. 2021 Aug 01.
    The impaired UPR-PMEL and TRP channels-autophagy axes in apoptotic melanocytes in vitiligo.
    Bo Xie, Xiuzu Song.
      Vitiligo is an autoimmune skin disease, characterized by depigmentation and epidermal melanocytes loss. The specific mechanisms underlying vitiligo have not been fully understood. As a result, treating vitiligo is a dermatological challenge. Recently, much attention has been paid to the dysfunction and interaction of organelles under environmental stress. The impaired organelles could generate misfolded proteins, particularly accumulated toxic premelanosome protein (PMEL) amyloid oligomers, activating the autoimmune system and cause melanocyte damage. Unfolded protein response (UPR) dysfunction accelerates toxic PMEL accumulation. Herein, we presented a narrative review on UPR's role in vitiligo, the misfolded PMEL-induced attack of the autoimmune system under autophagy dysfunction caused by abnormal activation of transient receptor potential (TRP) channels and the background of UPR system defects in melanocytes. All of these mechanisms were integrated to form UPR/PMEL-TRP channels/autophagy axis, providing a new understanding of vitiligo pathogenesis.
    Keywords:  autophagy; melanocyte; premelanosome protein; transient receptor potential channels; unfolded protein response; vitiligo
    DOI:  https://doi.org/10.1111/pcmr.13006
  67. Int Immunopharmacol. 2021 Aug 02. pii: S1567-5769(21)00469-0. [Epub ahead of print]98 107833
    Comparison of two routes of administration of a cationic liposome formulation for a prophylactic DC vaccination in a murine melanoma model.
    Mona Yazdani, Amin Reza Nikpoor, Zahra Gholizadeh, Nema Mohamadian Roshan, Alexander Seifalian, Mahmoud Reza Jaafari, Ali Badiee.
      Dendritic cell (DC) vaccination can be achieved via straight loading of vaccine into DCs ex vivo or administration to DCs in vivo. However, there is no certain consensus on which approach is preferable, and each strategy has its advantages and disadvantages, which affect the efficacy and safety of vaccines. It will also be more complicated when a vaccine delivery system is included. In this study, the efficacy of ex vivo pulsed DC-based vaccine compared with in vivo subcutaneous administration of a cationic liposomes (CLs) formulation containing gp100 antigen (gp100-CLs) was evaluated in a murine melanoma model. In combination with an anti-PD-1 antibody, the ex vivo approach of gp100-CLs yielded a significant (P < 0.01) increase in the number of antigen-specific tumors infiltrated lymphocytes (TILs) with a significant upregulation of IFN-γ (P < 0.0001) and PD-1 (P < 0.0001) expression level. They also dampened the function of immunosuppressive regulatory T cells (Tregs) via significant downregulation of IL-10 and TGF-β (P < 0.0001) expression level compared to in vivo approach in the tumor microenvironment (TME). Furthermore, prophylactic immunization with gp100-CLs pulsed DCs ex vivo delayed tumor growth and induced the survival benefit over in vivo immunization. Collectively, the ex vivo DC-based vaccination pulsed with gp100 encapsulated in liposomes synergizes with anti-PD-1 antibody and represents a preferable approach against melanoma.
    Keywords:  DOTAP; Liposome; Melanoma; PD-1 monoclonal antibody; Vaccine; gp100
    DOI:  https://doi.org/10.1016/j.intimp.2021.107833
  68. Antioxidants (Basel). 2021 Jul 05. pii: 1078. [Epub ahead of print]10(7):
    New Benzimidazothiazolone Derivatives as Tyrosinase Inhibitors with Potential Anti-Melanogenesis and Reactive Oxygen Species Scavenging Activities.
    Hee Jin Jung, Dong Chan Choi, Sang Gyun Noh, Heejeong Choi, Inkyu Choi, Il Young Ryu, Hae Young Chung, Hyung Ryong Moon.
      Thirteen (Z)-2-(substituted benzylidene)benzimidazothiazolone analogs were synthesized and evaluated for their inhibitory activity against mushroom tyrosinase. Among the compounds synthesized, compounds 1-3 showed greater inhibitory activity than kojic acid (IC50 = 18.27 ± 0.89 μM); IC50 = 3.70 ± 0.51 μM for 1; IC50 = 3.05 ± 0.95 μM for 2; and IC50 = 5.00 ± 0.38 μM for 3, and found to be competitive tyrosinase inhibitors. In silico molecular docking simulations demonstrated that compounds 1-3 could bind to the catalytic sites of tyrosinase. Compounds 1-3 inhibited melanin production and cellular tyrosinase activity in a concentration-dependent manner. Notably, compound 2 dose-dependently scavenged ROS in B16F10 cells. Furthermore, compound 2 downregulated the protein kinase A (PKA)/cAMP response element-binding protein (CREB) and mitogen-activated protein kinase (MAPK) signaling pathways, which led to a reduction in microphthalmia-associated transcription factor (MITF) expression, and decreased tyrosinase, tyrosinase related protein 1 (TRP1), and TRP2 expression, resulting in anti-melanogenesis activity. Hence, compound 2 may serve as an anti-melanogenic agent against hyperpigmentation diseases.
    Keywords:  benzimidazothiazolone; melanogenesis; reactive oxygen species (ROS); tyrosinase inhibitor
    DOI:  https://doi.org/10.3390/antiox10071078
  69. Int J Environ Res Public Health. 2021 Jul 27. pii: 7945. [Epub ahead of print]18(15):
    Gender-Dependent Specificities in Cutaneous Melanoma Predisposition, Risk Factors, Somatic Mutations, Prognostic and Predictive Factors: A Systematic Review.
    Oriana D'Ecclesiis, Saverio Caini, Chiara Martinoli, Sara Raimondi, Camilla Gaiaschi, Giulio Tosti, Paola Queirolo, Camilla Veneri, Calogero Saieva, Sara Gandini, Susanna Chiocca.
       BACKGROUND AND AIM: Over the last decades, the incidence of melanoma has been steadily growing, with 4.2% of the population worldwide affected by cutaneous melanoma (CM) in 2020 and with a higher incidence and mortality in men than in women. We investigated both the risk factors for CM development and the prognostic and predictive factors for survival, stratifying for both sex and gender.
    METHODS: We conducted a systematic review of studies indexed in PUB-MED, EMBASE, and Scopus until 4 February 2021. We included reviews, meta-analyses, and pooled analyses investigating differences between women and men in CM risk factors and in prognostic and predictive factors for CM survival.
    DATA SYNTHESIS: Twenty-four studies were included, and relevant data extracted. Of these, 13 studies concerned potential risk factors, six concerned predictive factors, and five addressed prognostic factors of melanoma.
    DISCUSSION: The systematic review revealed no significant differences in genetic predisposition to CM between males and females, while there appear to be several gender disparities regarding CM risk factors, partly attributable to different lifestyles and behavioral habits between men and women. There is currently no clear evidence of whether the mutational landscapes of CM differ by sex/gender. Prognosis is justified by a complex combination of phenotypes and immune functions, while reported differences between genders in predicting the effectiveness of new treatments are inconsistent. Overall, the results emerging from the literature reveal the importance of considering the sex/gender variable in all studies and pave the way for including it towards precision medicine.
    CONCLUSIONS: Men and women differ genetically, biologically, and by social construct. Our systematic review shows that, although fundamental, the variable sex/gender is not among the ones collected and analyzed.
    Keywords:  gender; melanoma; meta-analysis; precision medicine; predictive factors; prognostic factors; risk factors; sex; systematic review
    DOI:  https://doi.org/10.3390/ijerph18157945
  70. Aging Cell. 2021 Aug 06. e13447
    Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy.
    Valentin L'Hôte, Régis Courbeyrette, Guillaume Pinna, Jean-Christophe Cintrat, Gwenaëlle Le Pavec, Agnès Delaunay-Moisan, Carl Mann, Jean-Yves Thuret.
      The expression of BRAF-V600E triggers oncogene-induced senescence in normal cells and is implicated in the development of several cancers including melanoma. Here, we report that cardioglycosides such as ouabain are potent senolytics in BRAF senescence. Sensitization by ATP1A1 knockdown and protection by supplemental potassium showed that senolysis by ouabain was mediated by the Na,K-ATPase pump. Both ion transport inhibition and signal transduction result from cardioglycosides binding to Na,K-ATPase. An inhibitor of the pump that does not trigger signaling was not senolytic despite blocking ion transport, demonstrating that signal transduction is required for senolysis. Ouabain triggered the activation of Src, p38, Akt, and Erk in BRAF-senescent cells, and signaling inhibitors prevented cell death. The expression of BRAF-V600E increased ER stress and autophagy in BRAF-senescent cells and sensitized the cell to senolysis by ouabain. Ouabain inhibited autophagy flux, which was restored by signaling inhibitors. Consequently, we identified autophagy inhibitor chloroquine as a novel senolytic in BRAF senescence based on the mode of action of cardioglycosides. Our work underlies the interest of characterizing the mechanisms of senolytics to discover novel compounds and identifies the endoplasmic reticulum stress-autophagy tandem as a new vulnerability in BRAF senescence that can be exploited for the development of further senolytic strategies.
    Keywords:  Na,K-ATPase; Src; cardioglycosides; cellular senescence; endoplasmic reticulum stress; melanoma; senolytic
    DOI:  https://doi.org/10.1111/acel.13447
  71. J Cosmet Dermatol. 2021 Aug 01.
    Digit melanomas are associated with poor prognostic factors and unfavorable survivals.
    Faruk Tas, Kayhan Erturk.
       BACKGROUND: The anatomic location of primary melanoma is significantly associated with outcome.
    OBJECTIVE: To evaluate the prognostic factors and survival outcomes associated with melanomas on hand and foot digits.
    METHODS: The data of 106 patients with digit melanomas were analyzed retrospectively.
    RESULTS: Median age of patients was 55 years, and male-to-female ratio was one. Majority of the patients had skin melanomas (74.5%); and 25.5% of them had ungual melanomas. The lesions slightly more frequently affected toes (53.8%) and thumbs (55.9%); and 57.4% of the lesions were right-sided. Acral lentiginous melanoma was the major histological subtype (67.5%). Digit melanomas were associated with aggressive histological features, such as high Clark level (75%), thick Breslow depth (72.3%), presence of ulceration (74.3%), and high mitotic rate (58.3%). At admission, the rates of stage I-II, stage III, and stage IV diseases were 57.6%, 33%, and 9.4%, respectively. The recurrence and mortality rates were 41.7% and 46.2%, respectively. The 5-year RFS and OS rates were similar: 47%. Melanoma origins (skin vs. ungual), locations (finger vs. toe; first digit vs. others; and right vs. left), and histological subtypes (acral lentiginous melanoma vs. others) had no impact on survivals. The known poor prognostic histological factors, such as Clark level, Breslow thickness, mitotic rate, ulceration, and neurotropism, were found to be associated with both RFS and OS.
    CONCLUSION: Digit melanomas are associated with poor clinicopathological prognostic features, and they might predict unfavorable survivals.
    Keywords:  digit; finger; melanoma; prognostic factor; toe
    DOI:  https://doi.org/10.1111/jocd.14348
  72. Diagnostics (Basel). 2021 Jul 01. pii: 1198. [Epub ahead of print]11(7):
    18F-FDG PET/CT versus Diagnostic Contrast-Enhanced CT for Follow-Up of Stage IV Melanoma Patients Treated by Immune Checkpoint Inhibitors: Frequency and Management of Discordances over a 3-Year Period in a University Hospital.
    Jean-Baptiste Le Goubey, Charline Lasnon, Ines Nakouri, Laure Césaire, Michel de Pontville, Catherine Nganoa, Diane Kottler, Nicolas Aide.
       AIM: To perform a comprehensive analysis of discordances between contrast-enhanced CT (ceCT) and 18F-FDG PET/CT in the evaluation of the extra-cerebral treatment monitoring in patients with stage IV melanoma.
    MATERIALS AND METHODS: We conducted a retrospective monocentric observational study over a 3-year period in patients referred for 18F-FDG PET/CT and ceCT in the framework of therapy monitoring of immune checkpoint (ICIs) as of January 2017. Imaging reports were analyzed by two physicians in consensus. The anatomical site responsible for discordances, as well as induced changes in treatment were noted.
    RESULTS: Eighty patients were included and 195 pairs of scans analyzed. Overall, discordances occurred in 65 cases (33%). Eighty percent of the discordances (52/65) were due to 18F-FDG PET/CT scans upstaging the patient. Amongst these discordances, 17/52 (33%) led to change in patient's management, the most frequent being radiotherapy of a progressing site. ceCT represented 13/65 (20%) of discordances and induced changes in patients' management in 2/13 cases (15%). The most frequent anatomical site involved was subcutaneous for 18F-FDG PET/CT findings and lung or liver for ceCT.
    CONCLUSIONS: Treatment monitoring with 18F-FDG PET/CT is more efficient than ceCT and has a greater impact in patient's management.
    Keywords:  18F-FDG PET/CT; Immune checkpoint inhibitors; contrast-enhanced CT; follow-up; melanoma; metastases; therapy monitoring; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.3390/diagnostics11071198
  73. Indian J Pathol Microbiol. 2021 Jul-Sep;64(3):64(3): 535-540
    Melanoma of the central nervous system: A report of three cases.
    Pooja K Gajaria, Asha S Shenoy, Naina A Goel.
      Melanomas within the Central Nervous System (CNS) are most commonly metastatic lesions, with primary melanomas comprising only 0.05-0.07% of all brain tumors. We report three cases of primary CNS melanoma. The patients were young adults. There were two females and one male. On preoperative investigations, two cases were misdiagnosed to be angiomas on Magnetic Resonance Imaging (MRI). The melanotic nature of the lesion was an intraoperative observation. Pathologic examination showed features of malignancy with invasion of tumor cells into the brain parenchyma. In two patients, presence of systemic lesions were ruled out after surgery by whole-body Positron Emission Tomography (PET) scan. These patients were subject to adjuvant radiotherapy, while one patient succumbed immediately post-surgery. Primary CNS melanomas are rare with no defined treatment protocols. Histopathology diagnosis is crucial to rule out pigmented mimics.
    Keywords:  Brain; dura; melanoma; metastasis; primary
    DOI:  https://doi.org/10.4103/IJPM.IJPM_642_20
  74. JAMA Dermatol. 2021 Aug 04.
    Assessment of Diagnostic Accuracy of Dermoscopic Structures and Patterns Used in Melanoma Detection: A Systematic Review and Meta-analysis.
    Natalie M Williams, Kristina D Rojas, John M Reynolds, Deukwoo Kwon, Jackie Shum-Tien, Natalia Jaimes.
       Importance: Dermoscopy increases the diagnostic accuracy for melanoma. However, the accuracy of individual structures and patterns used in melanoma detection has not been systematically evaluated.
    Objective: To assess the diagnostic accuracy of individual dermoscopic structures and patterns used in melanoma detection.
    Data Sources: A search of Ovid Medline, Embase, Cochrane CENTRAL, Scopus, and Web of Science was conducted from inception to July 2020.
    Study Selection: Studies evaluating the dermoscopic structures and patterns among melanomas in comparison with nonmelanoma lesions were included. Excluded were studies with fewer than 3 patients, studies in languages other than English or Spanish, studies not reporting dermoscopic structures per lesion type, and studies assessing only nail, mucosal, acral, facial, or metastatic melanomas or melanomas on chronically sun-damaged skin. Multiple reviewers applied these criteria, and 0.7% of studies met selection criteria.
    Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline and Meta-analysis of Observational Studies in Epidemiology reporting guideline were followed. Guidelines were applied via independent extraction by multiple observers. Data were pooled using a random-effects model.
    Main Outcomes and Measures: The prespecified outcome measures were diagnostic accuracy (sensitivity and specificity) and risk (odds ratio [OR]) of melanoma for the following dermoscopic structures/patterns: atypical dots/globules, atypical network, blue-white veil, negative network, off-centered blotch, peripheral-tan structureless areas, atypical vessels (eg, linear irregular, polymorphous), pseudopods, streaks, regression (ie, peppering, scarlike areas), shiny white structures, angulated lines, irregular pigmentation, and a multicomponent pattern.
    Results: A total of 40 studies including 22 796 skin lesions and 5736 melanomas were evaluated. The structures and patterns with the highest ORs were shiny white structures (OR, 6.7; 95% CI, 2.5-17.9), pseudopods (OR, 6.7; 95% CI, 2.7-16.1), irregular pigmentation (OR, 6.4; 95% CI, 2.0-20.5), blue-white veil (OR, 6.3; 95% CI, 3.7-10.7), and peppering (OR, 6.3; 95% CI, 2.4-16.1). The structures with the highest specificity were pseudopods (97.3%; 95% CI, 94.3%-98.7%), shiny white structures (93.6%; 95% CI, 85.6%-97.3%), peppering (93.4%; 95% CI, 81.9%-97.8%), and streaks (92.1%; 95% CI, 88.4%-94.7%), whereas features with the highest sensitivity were irregular pigmentation (62.3%; 95% CI, 31.2%-85.8%), blue-white veil (60.6%; 95% CI, 46.7%-72.9%), atypical network (56.8%; 95% CI, 43.6%-69.2%), and a multicomponent pattern (53.7%; 95% CI, 40.4%-66.4%).
    Conclusions and Relevance: The findings of this systematic review and meta-analysis support the diagnostic importance of dermoscopic structures associated with melanoma detection (eg, shiny white structures, blue-white veil), further corroborate the importance of the overall pattern, and may suggest a hierarchy in the significance of these structures and patterns.
    DOI:  https://doi.org/10.1001/jamadermatol.2021.2845
  75. Nat Commun. 2021 Aug 05. 12(1): 4734
    Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment.
    Sandra S Ring, Jovana Cupovic, Lucas Onder, Mechthild Lütge, Christian Perez-Shibayama, Cristina Gil-Cruz, Elke Scandella, Angelina De Martin, Urs Mörbe, Fabienne Hartmann, Robert Wenger, Matthias Spiegl, Andrej Besse, Weldy V Bonilla, Felix Stemeseder, Sarah Schmidt, Klaus K Orlinger, Philippe Krebs, Burkhard Ludewig, Lukas Flatz.
      The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated a Cxcl13-expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation of Il33 gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells.
    DOI:  https://doi.org/10.1038/s41467-021-25057-w
  76. Biometals. 2021 Aug 05.
    Antiproliferative and antibacterial properties of biocompatible copper(II) complexes bearing chelating N,N-heterocycle ligands and potential mechanisms of action.
    Rodica Olar, Mihaela Badea, Mihaela Bacalum, Mina Răileanu, Lavinia L Ruţă, Ileana C Farcaşanu, Arpad Mihai Rostas, Ioana Dorina Vlaicu, Marcela Popa, Mariana Carmen Chifiriuc.
      In an attempt to propose new applications for the biomedical field, complexes with mixed ligands {[Cu(bpy)2(μ2OClO3)]ClO4}n (1) and [Cu(phen)2(OH2)](ClO4)2 (2) (bpy: 2,2'-biyridine; phen and 1,10-phenantroline) were evaluated for their antibacterial and cytotoxicicity features and for the elucidation of some of the mechanisms involved. Complex (2) proved to be a very potent antibacterial agent, exhibing MIC and MBEC values 2 to 54 times lower than those obtained for complex (1) against both susceptible or resistant Gram-positive and Gram-negative strains, in planktonic or biofilm growth state. In exchange, complex (1) exhibited selective cytotoxicity against melanoma tumor cells (B16), proving a promising potential for developing novel anticancer drugs. The possible mechanisms of both antimicrobial and antitumor activity of the copper(II) complexes is their DNA intercalative ability coupled with ROS generation. The obtained results recommend the two complexes for further development as multipurpose copper-containing drugs.
    Keywords:  1,10-Phenantroline; 2,2′-biyridine; Biofilm; Copper(ii) complex; DNA intercalation; Melanoma cells; Saccharomyces cerevisiae
    DOI:  https://doi.org/10.1007/s10534-021-00334-9
  77. Cureus. 2021 Jun;13(6): e15980
    Optic Disc Dose Comparison Between 125I and 103Pd Collaborative Ocular Melanoma Study (COMS) Plaques Based on Current Clinical Practice.
    Yongsook C Lee, Shih-Chi Lin, Yongbok Kim.
      Purpose The purpose of this study is to compare optic disc dose (ODD) between 125I and 103Pd Collaborative Ocular Melanoma Study (COMS) plaques in ocular brachytherapy. Methods A previously validated in-house brachytherapy dose calculation program was used for ODD calculations. ODD was calculated as a function of tumor margin-to-optic disc distance (DT) up to 5 mm for various tumor basal dimensions (BDs), for a prescription depth of 5 mm, and for standard and notched COMS plaques loaded with 125I (model: IAI-125A) and 103Pd (model: IAPd-103A) seeds. ODD calculations were repeated for prescription depths from 2 mm to 10 mm in 1 mm intervals. A prescribed dose of 85 Gy (irradiation time: 120 hours) was normalized to each prescription depth. Dose conversion factors (DCFs) for each prescription depth were calculated by taking a ratio of [total reference air kerma (TRAK) per seed]prescription depth to [TRAK per seed]5 mm. ODD reduction by notched COMS plaques was calculated for each prescription depth by subtracting ODD for notched COMS plaques from ODD for standard COMS plaques. Results Trends of ODD as a function of DT for various BDs are similar between the two seed types in both standard and notched COMS plaques. However, due to the energy difference, there exists a transition distance (dt) for each BD in each plaque at which ODD for 125I COMS plaques equals that for 103Pd COMS plaques. For small BDs, at DT <dt, ODD for 103Pd COMS plaques is higher than that for 125I COMS plaques while at DT >dt, the opposite is observed. For the largest 1-3 BD(s), contrarily, dt occurs within the tumor, and thus, ODD for 125I COMS plaquesis always higher. Trends of ODD reduction by notched COMS plaques as a function of DT for various BDs are the same for the two seed types except that maximum ODD reduction by 103Pd COMS notched plaques is larger. DCF increases with increasing prescription depth for both seed types. Conclusions There exist ODD differences between 125I and 103Pd COMS plaques and the differences depend on DT, BD, plaque size, and prescription depth.
    Keywords:  103pd; 125i; coms plaques; ocular brachytherapy; optic disc dose
    DOI:  https://doi.org/10.7759/cureus.15980
  78. Genes (Basel). 2021 Jul 16. pii: 1080. [Epub ahead of print]12(7):
    NGS Analysis of Liquid Biopsy (LB) and Formalin-Fixed Paraffin-Embedded (FFPE) Melanoma Samples Using Oncomine™ Pan-Cancer Cell-Free Assay.
    Magdalena Olbryt, Marcin Rajczykowski, Wiesław Bal, Anna Fiszer-Kierzkowska, Alexander Jorge Cortez, Magdalena Mazur, Rafał Suwiński, Wiesława Widłak.
      Next-generation sequencing (NGS) in liquid biopsies may contribute to the diagnosis, monitoring, and personalized therapy of cancer through the real-time detection of a tumor's genetic profile. There are a few NGS platforms offering high-sensitivity sequencing of cell-free DNA (cfDNA) samples. The aim of this study was to evaluate the Ion AmpliSeq HD Technology for targeted sequencing of tumor and liquid biopsy samples from patients with fourth-stage melanoma. Sequencing of 30 samples (FFPE tumor and liquid biopsy) derived from 14 patients using the Oncomine™ Pan-Cancer Cell-Free Assay was performed. The analysis revealed high concordance between the qPCR and NGS results of the BRAF mutation in FFPE samples (91%), as well as between the FFPE and liquid biopsy samples (91%). The plasma-tumor concordance of the non-BRAF mutations was 28%. A total of 17 pathogenic variants in 14 genes (from 52-gene panel), including TP53, CTNNB1, CCND1, MET, MAP2K1, and GNAS, were identified, with the CTNNB1S45F variant being the most frequent. A positive correlation between the LDH level and cfDNA concentration as well as negative correlation between the LDH level and time to progression was confirmed in a 22-patient cohort. The analysis showed both the potential and limitations of liquid biopsy genetic profiling using HD technology and the Ion Torrent platform.
    Keywords:  liquid biopsy; melanoma; targeted next-generation sequencing
    DOI:  https://doi.org/10.3390/genes12071080
  79. Cancers (Basel). 2021 Jul 23. pii: 3705. [Epub ahead of print]13(15):
    Systematic Roadmap for Cancer Drug Screening Using Zebrafish Embryo Xenograft Cancer Models: Melanoma Cell Line as a Case Study.
    Patricia Letrado, Holly Mole, María Montoya, Irene Palacios, Jorge Barriuso, Adam Hurlstone, Roberto Díez-Martínez, Julen Oyarzabal.
      Zebrafish embryo tumor transplant models are widely utilized in cancer research. Compared with traditional murine models, the small size and transparency of zebrafish embryos combined with large clutch sizes that increase statistical power and cheap husbandry make them a cost-effective and versatile tool for in vivo drug discovery. However, the lack of a comprehensive analysis of key factors impacting the successful use of these models impedes the establishment of basic guidelines for systematic screening campaigns. Thus, we explored the following crucial factors: (i) user-independent inclusion criteria, focusing on sample homogeneity; (ii) metric definition for data analysis; (iii) tumor engraftment criteria; (iv) image analysis versus quantification of human cancer cells using qPCR (RNA and gDNA); (v) tumor implantation sites; (vi) compound distribution (intratumoral administration versus alternative inoculation sites); and (vii) efficacy (intratumoral microinjection versus compound solution in media). Based on these analyses and corresponding assessments, we propose the first roadmap for systematic drug discovery screening in zebrafish xenograft cancer models using a melanoma cell line as a case study. This study aims to help the wider cancer research community to consider the adoption of this versatile model for cancer drug screening projects.
    Keywords:  cancer; drug discovery; roadmap; screening; xenograft; zebrafish
    DOI:  https://doi.org/10.3390/cancers13153705
  80. Am J Hum Genet. 2021 Jul 27. pii: S0002-9297(21)00270-6. [Epub ahead of print]
    A UVB-responsive common variant at chromosome band 7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor, AHR.
    Melanoma Meta-Analysis Consortium
      Genome-wide association studies (GWASs) have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). Because ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWASs identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. Because AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 introduced via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression and altering melanocyte growth phenotypes upon exposure.
    Keywords:  AHR; GWAS; UVR; aryl hydrocarbon receptor; eQTL; expression quantitative trait locus; fine-mapping; genome-wide association study; melanocyte; melanoma; tanning; ultraviolet radiation
    DOI:  https://doi.org/10.1016/j.ajhg.2021.07.002
  81. Front Cell Dev Biol. 2021 ;9 554831
    Transcription Factor DLX5 Promotes Hair Follicle Stem Cell Differentiation by Regulating the c-MYC/microRNA-29c-3p/NSD1 Axis.
    Bojie Lin, Jiangying Zhu, Guoqian Yin, Mingde Liao, Guanyu Lin, Yuyong Yan, Dan Huang, Siding Lu.
       Introduction: Adult stem cell function has been one of the most intensively explored areas of biological and biomedical research, with hair follicle stem cells serving as one of the best model systems. This study explored the role of the transcription factor DLX5 in regulating hair follicle stem cell (HFSC) differentiation.
    Methods: HFSCs were isolated, characterized, and assessed for their expression of DLX5, c-MYC, NSD1, and miR-29c-3p using RT-qPCR, Western blot analysis, or immunofluorescence. Next, the ability of HFSCs to proliferate as well as differentiate into either sebaceous gland cells or epidermal cells was determined. The binding of DLX5 to the c-MYC promoter region, the binding of c-MYC to the miR-29c-3p promoter region, and the binding of miR-29c-3p to the 3'-UTR of NSD1 mRNA were verified by luciferase activity assay and ChIP experiments.
    Results: DLX5 was highly expressed in differentiated HFSCs. DLX5 transcriptionally activated c-MYC expression to induce HFSC differentiation. c-MYC was able to bind the miR-29c-3p promoter and thus suppressed its expression. Without miR-29c-3p mediated suppression, NSD1 was then able to promote HFSC differentiation. These in vitro experiments suggested that DLX5 could promote HFSC differentiation via the regulation of the c-MYC/miR-29c-3p/NSD1 axis.
    Discussion: This study demonstrates that DLX5 promotes HFSC differentiation by modulating the c-MYC/miR-29c-3p/NSD1 axis and identifies a new mechanism regulating HFSC differentiation.
    Keywords:  DLX5; Hair follicle stem cells; NSD1; c-Myc; microRNA-29c-3p
    DOI:  https://doi.org/10.3389/fcell.2021.554831
  82. Int J Dermatol. 2021 Aug 05.
    Confocal microscopy, dermoscopy, and histopathology features of atypical intraepidermal melanocytic proliferations associated with evolution to melanoma in situ.
    Lilian K F L Rocha, Ricardo E Vilain, Richard A Scolyer, Serine N Lo, Martin Drummond, Phoebe Star, Gerald B Fogarty, Angela M Hong, Pascale Guitera.
       BACKGROUND: Atypical intraepidermal melanocytic proliferations (AIMP) is a descriptive term sometimes applied to biopsies that do not fulfill diagnostic criteria of melanoma. They are common on sun-damaged skin, but their definition and management are controversial.
    OBJECTIVE: To describe dermoscopic (DS), reflectance confocal microscopic (RCM) and histopathological features of AIMP and identify features associated with subsequent melanoma in situ (MIS).
    METHODS: A retrospective analysis of AIMP lesions correlated with patient outcome at two melanoma tertiary centers between 2005 and 2015.
    RESULTS: Thirty-four patients were included. Nine (26%) patients had MIS in subsequent biopsies. Predictors of later MIS were target-like pattern (OR:12.0 [CI: 1.23, 117.41]; P = 0.032) and high-density vascular network (OR:12 [CI: 1.23-117.41], P: 0.032) on DS, and presence of dendritic cells touching each other (OR:9.1 [CI: 1.54, 54.59], P = 0.014) on RCM. Clinical predictors of worse outcome included a previous history of MIS at the same site. Radiotherapy for AIMP had a high failure rate (all patients presented with recurrent disease, three as AIMP and two as MIS).
    CONCLUSIONS: Considering that most cases in this series received non-surgical treatment at baseline, we recommend close monitoring for lesions with target-like pattern and density vascular network on DS and treatment for lesions with progression of atypia and/or with "confluent" dendritic cells on RCM. Although the number of patients in this series is very low, early surgery is recommended for MIS cases that recur as AIMP.
    DOI:  https://doi.org/10.1111/ijd.15815
  83. Genes (Basel). 2021 Jul 19. pii: 1093. [Epub ahead of print]12(7):
    Behind the Scene: Exploiting MC1R in Skin Cancer Risk and Prevention.
    Michele Manganelli, Stefania Guida, Anna Ferretta, Giovanni Pellacani, Letizia Porcelli, Amalia Azzariti, Gabriella Guida.
      Melanoma and non-melanoma skin cancers (NMSCs) are the most frequent cancers of the skin in white populations. An increased risk in the development of skin cancers has been associated with the combination of several environmental factors (i.e., ultraviolet exposure) and genetic background, including melanocortin-1 receptor (MC1R) status. In the last few years, advances in the diagnosis of skin cancers provided a great impact on clinical practice. Despite these advances, NMSCs are still the most common malignancy in humans and melanoma still shows a rising incidence and a poor prognosis when diagnosed at an advanced stage. Efforts are required to underlie the genetic and clinical heterogeneity of melanoma and NMSCs, leading to an optimization of the management of affected patients. The clinical implications of the impact of germline MC1R variants in melanoma and NMSCs' risk, together with the additional risk conferred by somatic mutations in other peculiar genes, as well as the role of MC1R screening in skin cancers' prevention will be addressed in the current review.
    Keywords:  MC1R; basal cell carcinoma; melanocortin 1 receptor; melanoma; skin cancer prevention; squamous cell
    DOI:  https://doi.org/10.3390/genes12071093
  84. Clin Rev Allergy Immunol. 2021 Aug 06.
    Correction to: Clinical Features, Immunopathogenesis, and Therapeutic Strategies in Vitiligo.
    Yinghan Wang, Shuli Li, Chunying Li.
      
    DOI:  https://doi.org/10.1007/s12016-021-08884-z
  85. J Invest Dermatol. 2021 Jul 31. pii: S0022-202X(21)01660-2. [Epub ahead of print]
    Increased activation of innate immunity and pro-apoptotic CXCR3B in 'normal-appearing' skin on the lesional side of patients with segmental vitiligo.
    Thierry Passeron, Valentina Ea Malmqvst, Hanene Bzioueche, Sandrine Marchetti, Stephane Rocchi, Meri K Tulic.
      
    Keywords:  CXCR3B; innate immunity; melanocytes; segmental vitiligo
    DOI:  https://doi.org/10.1016/j.jid.2021.07.157
  86. Antioxidants (Basel). 2021 Jul 15. pii: 1129. [Epub ahead of print]10(7):
    Arbutin as a Skin Depigmenting Agent with Antimelanogenic and Antioxidant Properties.
    Yong Chool Boo.
      Arbutin is a compound of hydroquinone and D-glucose, and it has been over 30 years since there have been serious studies on the skin lightening action of this substance. In the meantime, there have been debates and validation studies about the mechanism of action of this substance as well as its skin lightening efficacy and safety. Several analogs or derivatives of arbutin have been developed and studied for their melanin synthesis inhibitory action. Formulations have been developed to improve the stability, transdermal delivery, and release of arbutin, and device usage to promote skin absorption has been developed. Substances that inhibit melanin synthesis synergistically with arbutin have been explored. The skin lightening efficacy of arbutin alone or in combination with other active ingredients has been clinically evaluated. Combined therapy with arbutin and laser could give enhanced depigmenting efficacy. The use of arbutin causes dermatitis rarely, and caution is recommended for the use of arbutin-containing products, especially from the viewpoint that hydroquinone may be generated during product use. Studies on the antioxidant properties of arbutin are emerging, and these antioxidant properties are proposed to contribute to the skin depigmenting action of arbutin. It is hoped that this review will help to understand the pros and cons of arbutin as a cosmetic ingredient, and will lead to future research directions for developing advanced skin lightening and protecting cosmetic products.
    Keywords:  antioxidant; arbutin; cosmetic; hyperpigmentation; melanin; melasma; nuclear factor erythroid 2-related factor 2 (Nrf2); pigment; skin lightening; tyrosinase
    DOI:  https://doi.org/10.3390/antiox10071129
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