bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒08‒09
thirty papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Cancer Res. 2020 Aug 01. 80(15): 3070-3071
    Carpenter ES, Steele NG, Pasca di Magliano M.
      Pancreatic cancer is characterized by an extensive and complex microenvironment, and is resistant to both chemotherapy and immune checkpoint blockade. The study by Principe and colleagues in this issue of Cancer Research proposes a combinatorial approach based on targeting the very mechanisms of resistance to gemcitabine, a commonly used chemotherapeutic agent. The authors show that gemcitabine treatment causes profound changes in the pancreatic cancer microenvironment, including elevated TGFβ signaling and immune checkpoint expression, as well as increased antigen presentation in tumor cells. Accordingly, they show that the combination of chemotherapy, TGFβ signaling inhibition, and immune checkpoint blockade effectively restores antitumor immunity and results in a significant survival benefit.See related article by Principe et al., p. 3101.
  2. Mol Cancer. 2020 Aug 05. 19(1): 119
    Ma S, Kong S, Wang F, Ju S.
      Targeted treatment, which can specifically kill tumour cells without affecting normal cells, is a new approach for tumour therapy. However, tumour cells tend to acquire resistance to targeted drugs during treatment. Circular RNAs (circRNAs) are single-stranded RNA molecules with unique structures and important functions. With the development of RNA sequencing technology, circRNAs have been found to be widespread in tumour-resistant cells and to play important regulatory roles. In this review, we present the latest advances in circRNA research and summarize the various mechanisms underlying their regulation. Moreover, we review the role of circRNAs in the chemotherapeutic resistance of tumours and explore the clinical value of circRNA regulation in treating tumour resistance.
    Keywords:  Circular RNAs (CircRNAs); Functions; Self-circularize; Targeted treatment; Tumor resistance
  3. Anticancer Agents Med Chem. 2020 Jul 30.
    Zahan T, Das PK, Akter SF, Habib R, Rahman MH, Karim MR, Islam F.
      BACKGROUND: Chemo resistance is a vital problem in cancer therapy where cancer cells develop mechanisms to encounter the effect of chemo therapeutics, resulting in cancer recurrence. In addition, chemotherapy-resistant lead to the formation of a more aggressive form of cancer cells, which in turn contribute to the poor survival of patients with cancer.OBJECTIVE: In this review, we aimed to provide an overview of how the therapy resistance property evolves in cancer cells, contributing factors and their role in cancer chemo resistance, and exemplified the problems of some available therapies.
    METHODS: The published literatures on various electronic databases including, Pubmed, Scopus, Google scholar containing keywords cancer therapy resistance, phenotypic, metabolic and epigentic factors, were vigorously searched, retrieved and analyzed.
    RESULTS: Cancer cells have developed a range of cellular processes, including uncontrolled activation of epithelial-mesenchymal transition (EMT), metabolic reprogramming and epigenetic alterations. These cellular processes play significant roles in the generation of therapy resistance. Furthermore, the micro environment where cancer cells evolve effectively contributes to the process of chemo resistance. In tumour micro environment immune cells, mesenchymal stem cells (MSCs), endothelial cells and cancer-associated fibroblasts (CAFs) contribute to the maintenance of therapy-resistant phenotype via the secretion of factors that promote resistance to chemotherapy.
    CONCLUSION: To conclude, as these factors hinder successful cancer therapies, therapeutic resistance property of cancer cells is a subject of intense research,which in turn could open new horizon to aims for developing efficient therapies.
    Keywords:  EMT; Therapy resistance; cancer heterogeneity; metabolic reprogramming; therapeutic options.; tumour micro environment
  4. Proc Natl Acad Sci U S A. 2020 Aug 03. pii: 201918986. [Epub ahead of print]
    Li N, Kang Y, Wang L, Huff S, Tang R, Hui H, Agrawal K, Gonzalez GM, Wang Y, Patel SP, Rana TM.
      Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N6 -methylation of adenosine (m6A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m6A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m6A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m6A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.
    Keywords:  GVAX; PD-1 blockade; immunotherapy enhancers; m6A RNA modification; melanoma
  5. Front Mol Biosci. 2020 ;7 130
    Tiwari R, Manzar N, Ateeq B.
      Despite the current advances in the treatment for prostate cancer, the patients often develop resistance to the conventional therapeutic interventions. Therapy-induced drug resistance and tumor progression have been associated with cellular plasticity acquired due to reprogramming at the molecular and phenotypic levels. The plasticity of the tumor cells is mainly governed by two factors: cell-intrinsic and cell-extrinsic. The cell-intrinsic factors involve alteration in the genetic or epigenetic regulators, while cell-extrinsic factors include microenvironmental cues and drug-induced selective pressure. Epithelial-mesenchymal transition (EMT) and stemness are two important hallmarks that dictate cellular plasticity in multiple cancer types including prostate. Emerging evidence has also pinpointed the role of tumor cell plasticity in driving anti-androgen induced neuroendocrine prostate cancer (NEPC), a lethal and therapy-resistant subtype. In this review, we discuss the role of cellular plasticity manifested due to genetic, epigenetic alterations and cues from the tumor microenvironment, and their role in driving therapy resistant prostate cancer.
    Keywords:  ADT; EMT; NEPC; cellular plasticity; drug resistance; prostate cancer; stemness
  6. Cancer Discov. 2020 Aug;10(8): 1094-1096
    Koleilat MK, Kwong LN.
      The discovery of covalent inhibitors of KRASG12C has led to promising clinical results in lung cancer, but disappointing response rates in colon cancer. In this issue of Cancer Discovery, Misale and colleagues identify high endogenous EGFR activity as the underlying mechanism of intrinsic resistance, which can be overcome by anti-EGFR antibody coadministration.See related article by Amodio et al., p. 1129.
  7. Cancer Res. 2020 Aug 03. pii: canres.1830.2020. [Epub ahead of print]
    Krais JJ, Johnson N.
      Cancers that arise from BRCA1 germline mutations are deficient for homologous recombination (HR) DNA repair and are sensitive to DNA damaging agents such as platinum and PARP inhibitors (PARPi). In vertebrate organisms, knockout of critical HR genes including BRCA1 and BRCA2 is lethal because HR is required for genome replication. Thus, cancers must develop strategies to cope with loss of HR activity. Furthermore, as established tumors respond to chemotherapy selection pressure, additional genetic adaptations transition cancers to an HR-proficient state. In this review, we discuss biological mechanisms that influence the ability of BRCA1-mutant cancers to perform HR. Furthermore, we consider how the HR status fluctuates throughout the cancer life course, from tumor initiation to the development of therapy refractory disease.
  8. Mol Cancer Res. 2020 Aug 04. pii: molcanres.0075.2020. [Epub ahead of print]
    Song W, Kim LC, Han W, Hou Y, Edwards D, Wang S, Blackwell TS, Cheng F, Brantley-Sieders DM, Chen J.
      EphA2 receptor tyrosine kinase (RTK) is often expressed at high levels in cancer and has been shown to regulate tumor growth and metastasis across multiple tumor types, including non-small cell lung cancer. A number of signaling pathways downstream of EphA2 RTK have been identified; however, mechanisms of EphA2's proximal downstream signals are less well-characterized. In this study, we used a yeast-two-hybrid screen to identify PLCγ1 as a novel EphA2 interactor. EphA2 interacts with PLCγ1 and the kinase activity of EphA2 was required for phosphorylation of PLCγ1. In human lung cancer cells, genetic or pharmacological inhibition of EphA2 decreased phosphorylation of PLCγ1 and loss of PLCγ1 inhibited tumor cell growth in vitro. Knockout of PLCγ1 by CRISPR-mediated genome editing also impaired tumor growth in a KrasG12D-p53-Lkb1 murine lung tumor model. Collectively, these data show that the EphA2-PLCγ1 signaling axis promotes tumor growth of lung cancer and provides rationale for disruption of this signaling axis as a potential therapeutic option. Implications: The EphA2-PLCG1 signaling axis promotes tumor growth of non-small cell lung cancer and can potentially be targeted as a therapeutic option.
  9. EMBO Rep. 2020 Aug 04. e50446
    Matafora V, Farris F, Restuccia U, Tamburri S, Martano G, Bernardelli C, Sofia A, Pisati F, Casagrande F, Lazzari L, Marsoni S, Bonoldi E, Bachi A.
      Melanoma progression is generally associated with increased transcriptional activity mediated by the Yes-associated protein (YAP). Mechanical signals from the extracellular matrix are sensed by YAP, which then activates the expression of proliferative genes, promoting melanoma progression and drug resistance. Which extracellular signals induce mechanotransduction, and how this is mediated, is not completely understood. Here, using secretome analyses, we reveal the extracellular accumulation of amyloidogenic proteins, i.e. premelanosome protein (PMEL), in metastatic melanoma, together with proteins that assist amyloid maturation into fibrils. We also confirm the accumulation of amyloid-like aggregates, similar to those detected in Alzheimer disease, in metastatic cell lines, as well as in human melanoma biopsies. Mechanistically, beta-secretase 2 (BACE2) regulates the maturation of these aggregates, which in turn induce YAP activity. We also demonstrate that recombinant PMEL fibrils are sufficient to induce mechanotransduction, triggering YAP signaling. Finally, we demonstrate that BACE inhibition affects cell proliferation and increases drug sensitivity, highlighting the importance of amyloids for melanoma survival, and the use of beta-secretase inhibitors as potential therapeutic approach for metastatic melanoma.
    Keywords:  BACE2; amyloid; mechanosignaling; metastasis; secretome
  10. Cell Metab. 2020 Jul 30. pii: S1550-4131(20)30367-3. [Epub ahead of print]
    van Gastel N, Spinelli JB, Sharda A, Schajnovitz A, Baryawno N, Rhee C, Oki T, Grace E, Soled HJ, Milosevic J, Sykes DB, Hsu PP, Vander Heiden MG, Vidoudez C, Trauger SA, Haigis MC, Scadden DT.
      Cancer relapse begins when malignant cells pass through the extreme metabolic bottleneck of stress from chemotherapy and the byproducts of the massive cell death in the surrounding region. In acute myeloid leukemia, complete remissions are common, but few are cured. We tracked leukemia cells in vivo, defined the moment of maximal response following chemotherapy, captured persisting cells, and conducted unbiased metabolomics, revealing a metabolite profile distinct from the pre-chemo growth or post-chemo relapse phase. Persisting cells used glutamine in a distinctive manner, preferentially fueling pyrimidine and glutathione generation, but not the mitochondrial tricarboxylic acid cycle. Notably, malignant cell pyrimidine synthesis also required aspartate provided by specific bone marrow stromal cells. Blunting glutamine metabolism or pyrimidine synthesis selected against residual leukemia-initiating cells and improved survival in leukemia mouse models and patient-derived xenografts. We propose that timed cell-intrinsic or niche-focused metabolic disruption can exploit a transient vulnerability and induce metabolic collapse in cancer cells to overcome chemoresistance.
    Keywords:  acute myeloid leukemia; aspartate; bone marrow niche; cell metabolism; chemotherapy; glutamine; mouse models; patient-derived xenografts; pyrimidine synthesis; tumor microenvironment
  11. Mol Cancer. 2020 Aug 06. 19(1): 120
    Wu SY, Fu T, Jiang YZ, Shao ZM.
      The tumor microenvironment is highly complex, and immune escape is currently considered an important hallmark of cancer, largely contributing to tumor progression and metastasis. Named for their capability of killing target cells autonomously, natural killer (NK) cells serve as the main effector cells toward cancer in innate immunity and are highly heterogeneous in the microenvironment. Most current treatment options harnessing the tumor microenvironment focus on T cell-immunity, either by promoting activating signals or suppressing inhibitory ones. The limited success achieved by T cell immunotherapy highlights the importance of developing new-generation immunotherapeutics, for example utilizing previously ignored NK cells. Although tumors also evolve to resist NK cell-induced cytotoxicity, cytokine supplement, blockade of suppressive molecules and genetic engineering of NK cells may overcome such resistance with great promise in both solid and hematological malignancies. In this review, we summarized the fundamental characteristics and recent advances of NK cells within tumor immunometabolic microenvironment, and discussed potential application and limitations of emerging NK cell-based therapeutic strategies in the era of presicion medicine.
    Keywords:  Immunometabolism; Immunotherapy; Innate immunity; Natural killer cell; Precision treatment; Tumor progression
  12. Sci Transl Med. 2020 Aug 05. pii: eaax8313. [Epub ahead of print]12(555):
    Lupo B, Sassi F, Pinnelli M, Galimi F, Zanella ER, Vurchio V, Migliardi G, Gagliardi PA, Puliafito A, Manganaro D, Luraghi P, Kragh M, Pedersen MW, Horak ID, Boccaccio C, Medico E, Primo L, Nichol D, Spiteri I, Heide T, Vatsiou A, Graham TA, Élez E, Argiles G, Nuciforo P, Sottoriva A, Dienstmann R, Pasini D, Grassi E, Isella C, Bertotti A, Trusolino L.
      Blockade of epidermal growth factor receptor (EGFR) causes tumor regression in some patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs typically remain even after maximal response to therapy, leading to relapse. Using patient-derived xenografts (PDXs), we observed that mCRC cells surviving EGFR inhibition exhibited gene expression patterns similar to those of a quiescent subpopulation of normal intestinal secretory precursors with Paneth cell characteristics. Compared with untreated tumors, these pseudodifferentiated tumor remnants had reduced expression of genes encoding EGFR-activating ligands, enhanced activity of human epidermal growth factor receptor 2 (HER2) and HER3, and persistent signaling along the phosphatidylinositol 3-kinase (PI3K) pathway. Clinically, properties of residual disease cells from the PDX models were detected in lingering tumors of responsive patients and in tumors of individuals who had experienced early recurrence. Mechanistically, residual tumor reprogramming after EGFR neutralization was mediated by inactivation of Yes-associated protein (YAP), a master regulator of intestinal epithelium recovery from injury. In preclinical trials, Pan-HER antibodies minimized residual disease, blunted PI3K signaling, and induced long-term tumor control after treatment discontinuation. We found that tolerance to EGFR inhibition is characterized by inactivation of an intrinsic lineage program that drives both regenerative signaling during intestinal repair and EGFR-dependent tumorigenesis. Thus, our results shed light on CRC lineage plasticity as an adaptive escape mechanism from EGFR-targeted therapy and suggest opportunities to preemptively target residual disease.
  13. Cancer Res. 2020 Aug 03. pii: canres.0141.2020. [Epub ahead of print]
    Pulido I, Ollosi S, Aparisi S, Becker JH, Aliena-Valero A, Benet M, Rodríguez ML, López A, Tamayo-Torres E, Chuliá-Peris L, García-Cañaveras JC, Soucheray M, Dalheim AV, Salom JB, Qiu W, Kaja S, Alcácer Fernández-Coronado J, Alandes S, Alcácer J, Al-Shahrour F, Borgia JA, Juan O, Nishimura MI, Lahoz A, Carretero J, Shimamura T.
      Progression on therapy in NSCLC is often evaluated radiographically; however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated EGFR promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results. These trials were based on a hypothesis that the EDN1-EDNR axis activates the MAPK-ERK signaling pathway that is vital to the cancer cell survival; the trials were not designed to evaluate the impact of tumor-derived EDN1 in modifying tumor microenvironment or contributing to drug resistance. Ectopic overexpression of EDN1 in cells with mutated EGFR resulted in poor drug delivery and retarded growth in vivo but not in vitro. Intratumoral injection of rEDN significantly reduced blood flow and subsequent gefitinib accumulation in xenografted EGFR mutant tumors. Furthermore, depletion of EDN1 or the use of endothelin receptor inhibitors bosentan and ambrisentan improved drug penetration into tumors and restored blood flow in tumor-associated vasculature. Correlatively, these results describe a simplistic endogenous yet previously unrealized resistance mechanism inherent to a subset of EGFR-mutant NSCLC to attenuate TKI delivery to the tumors by limiting drug-carrying blood flow and the drug concentration in tumors.
  14. Nat Commun. 2020 Aug 06. 11(1): 3904
    Gao X, Wang Q, Wang Y, Liu J, Liu S, Liu J, Zhou X, Zhou L, Chen H, Pan L, Chen J, Wang D, Zhang Q, Shen S, Xiao Y, Wu Z, Cheng Y, Chen G, Krubra S, Qin J, Huang L, Zhang P, Wang C, Moses RE, Lonard DM, Malley BWO, Fares F, Zhang B, Li X, Li L, Xiao J.
      A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGγ-proteasome, attenuates cancer cell growth and sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGγ via an evolutionarily-conserved serine-rich domain with 4-serine phosphorylation. We find the cyclin-dependent phosphatase CDC25A is a key regulator for NIP30 phosphorylation and modulation of REGγ activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGγ mediated regulation of the REGγ target protein p21 in vivo using p53-/- and p53/REGγ double-deficient mice. Moreover, Phosphor-NIP30 mimetics significantly increase the growth inhibitory effect of chemotherapeutic agents in vitro and in vivo. Given that NIP30 is frequently mutated in the TCGA cancer database, our results provide insight into the regulatory pathway controlling the REGγ-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.
  15. Theranostics. 2020 ;10(19): 8903-8923
    Wu JE, Wu YY, Tung CH, Tsai YT, Chen HY, Chen YL, Hong TM.
      The loss of cancer-cell junctions and escape from the primary-tumor microenvironment are hallmarks of metastasis. A tight-junction protein, Claudin 1 (CLDN1), is a metastasis suppressor in lung adenocarcinoma. However, as a metastasis suppressor, the underlying molecular mechanisms of CLDN1 has not been well studied. Methods: The signaling pathway regulated by CLDN1 was analyzed by Metacore software and validated by immunoblots. The effect of the CLDN1-EPHB6-ERK-SLUG axis on the formation of cancer stem-like cells, drug resistance and metastasis were evaluated by sphere assay, aldefluor assay, flow cytometry, migration assay, cytotoxicity, soft agar assay, immunoprecipitation assay and xenograft experiments. Furthermore, the methylation-specific PCR, pyrosequencing assay, chromatin immunoprecipitation and reporter assay were used to study the epigenetic and RUNX3-mediated CLDN1 transcription. Finally, the molecular signatures of RUNX3/CLDN1/SLUG were used to evaluate the correlation with overall survival by using gene expression omnibus (GEO) data. Results: We demonstrated that CLDN1 repressed cancer progression via a feedback loop of the CLDN1-EPHB6-ERK1/2-SLUG axis, which repressed metastasis, drug resistance, and cancer stemness, indicating that CLDN1 acts as a metastasis suppressor. CLDN1 upregulated the cellular level of EPHB6 and enhanced its activation, resulting in suppression of ERK1/2 signaling. Interestingly, DNA hypermethylation of the CLDN1 promoter abrogated SLUG-mediated suppression of CLDN1 in low-metastatic cancer cells. In contrast, the histone deacetylase inhibitor trichostatin A or vorinostat facilitated CLDN1 expression in high-metastatic cancer cells and thus increased the efficacy of chemotherapy. Combined treatment with cisplatin and trichostatin A or vorinostat had a synergistic effect on cancer-cell death. Conclusions: This study revealed that DNA methylation maintains CLDN1 expression and then represses lung cancer progression via the CLDN1-EPHB6-ERK1/2-SLUG axis. Because CLDN1 enhances the efficacy of chemotherapy, CLDN1 is not only a prognostic marker but a predictive marker for lung adenocarcinoma patients who are good candidates for chemotherapy. Forced CLDN1 expression in low CLDN1-expressing lung adenocarcinoma will increase the chemotherapy response, providing a novel therapeutic strategy.
    Keywords:  CLDN1; DNA methylation; cancer stem-like cells; drug resistance; metastasis.
  16. Mol Cancer Res. 2020 Aug 04. pii: molcanres.0180.2020. [Epub ahead of print]
    Li S, Liu F, Xu L, Li C, Yang X, Guo B, Gu J, Wang L.
      Gastric cancer (GC) remains the third leading cause of cancer-related death, and tumor metastasis is the main risk factor for poor prognosis of GC patients. Transcription factor EB (TFEB) is a MiT family member and has been found to drive tumorigenesis in a number of tissues, while few studies were focused on investigating its pro-metastasis role and mechanism in GC. Here, we found TFEB was upregulated in GC tissues compared with adjacent normal gastric epithelial tissues. Immunohistochemical analysis from GC tissue microarray revealed that TFEB in GC was correlated with depth of tumor invasion, lymph node or distant metastasis, tumor TNM stage and overall survival. GC cells with TFEB overexpression presented an increased cell migration or invasion, and epithelial-mesenchymal transition. Furthermore, gene correlation analysis and Gene Set Enrichment Analysis enriched Wnt/β-catenin signaling pathway members in TFEB high-expression group, and the TOP/FOPflash assay verified the effect of TFEB on β-catenin transcription activity. Besides, we found that TFEB could trigger the aggregation of β-catenin in nucleus and activate its transcription, as well as facilitate the expression of Wnt/β-catenin target genes and EMT-related markers, which could be reversed by the Wnt/β-catenin inhibitor XAV-939. Collectively, TFEB enhances GC metastatic potential by activating Wnt/β-catenin signaling pathway and may become a promising therapeutic target for GC metastasis. Implications: Overexpressed TFEB predicts a higher rate of metastasis and worse survival in GC patients. Mechanistically, TFEB activates Wnt/β-catenin signaling to fuel migratory and invasive activities of GC cells, as well as EMT.
  17. Cancer Discov. 2020 Aug 05.
      New androgen receptor binding sites acquired with metastasis overlapped with those in fetal tissue.
  18. Cancer Res. 2020 Aug 01. 80(15): 3072-3073
    Kuijjer ML.
      One of the biggest challenges in cancer is predicting its initiation and course of progression. In this issue of Cancer Research, Rockne and colleagues use state transition theory to predict how peripheral mononuclear blood cells in mice transition from a healthy state to acute myeloid leukemia. They found that critical transcriptomic perturbations could predict initiation and progression of the disease. This is an important step toward accurately predicting cancer evolution, which may eventually facilitate early diagnosis of cancer and disease recurrence, and which could potentially inform on timing of therapeutic interventions.See related article by Rockne et al., 3157.
  19. Ann Oncol. 2020 Jul 30. pii: S0923-7534(20)39992-0. [Epub ahead of print]
    Tetzlaff MT, Adhikari C, Lo S, Rawson RV, Amaria RN, Menzies AM, Wilmott JS, Ferguson PM, Ross MI, Spillane AJ, Vu KA, Ma J, Ning J, Haydu L, Saw RPM, Wargo JA, Tawbi HA, Gershenwald JE, Long GV, Davies MA, Scolyer RA.
      BACKGROUND: Recent clinical trials demonstrated safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse.METHODS: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes.
    RESULTS: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (p=0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (p=0.014), whereas necrosis (p=0.012) and/or immature/proliferative fibrosis (p=0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (p=0.035).
    CONCLUSIONS: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.
    Keywords:  melanoma; neoadjuvant; pathology; therapy; treatment
  20. Cell Rep. 2020 Aug 04. pii: S2211-1247(20)30979-7. [Epub ahead of print]32(5): 107994
    Vaishnavi A, Scherzer MT, Kinsey CG, Parkman GL, Truong A, Ghazi P, Schuman S, Battistone B, Garrido-Laguna I, McMahon M.
      NTRK1 gene fusions are actionable drivers of numerous human malignancies. Here, we show that expression of the TPR-NTRK1 fusion kinase in immortalized mouse pancreatic ductal epithelial (IMPE) (pancreas) or mouse lung epithelial (MLE-12) cells is sufficient to promote rapidly growing tumors in mice. Both tumor models are exquisitely sensitive to targeted inhibition with entrectinib, a tropomyosin-related kinase A (TRKA) inhibitor. Initial regression of NTRK1-driven tumors is driven by induced expression of BIM, such that BIM silencing leads to a diminished response to entrectinib in vivo. However, the emergence of drug-resistant disease limits the long-term durability of responses. Based on the reactivation of RAF>MEK>ERK signaling observed in entrectinib-treated tumors, we show that the combination of entrectinib plus the MEK1/2 inhibitor cobimetinib dramatically forestalls the onset of drug resistance in vivo. Collectively, these data provide a mechanistic rationale for rapid clinical deployment of combined inhibition of TRKA plus MEK1/2 in NTRK1-driven cancers.
    Keywords:  NTRK gene fusion; colorectal cancer; kinase oncoproteins; lung cancer; pancreatic cancer; pathway-targeted therapies
  21. Cancers (Basel). 2020 Jul 31. pii: E2122. [Epub ahead of print]12(8):
    Lee KL, Chen G, Chen TY, Kuo YC, Su YK.
      A higher propensity of developing brain metastasis exists in triple-negative breast cancer (TNBC). Upon comparing the metastatic patterns of all breast cancer subtypes, patients with TNBC exhibited increased risks of the brain being the initial metastatic site, early brain metastasis development, and shortest brain metastasis-related survival. Notably, the development of brain metastasis differs from that at other sites owing to the brain-unique microvasculature (blood brain barrier (BBB)) and intracerebral microenvironment. Studies of brain metastases from TNBC have revealed the poorest treatment response, mostly because of the relatively backward strategies to target vast disease heterogeneity and poor brain efficacy. Moreover, TNBC is highly associated with the existence of cancer stem cells (CSCs), which contribute to circulating cancer cell survival before BBB extravasation, evasion from immune surveillance, and plasticity in adaptation to the brain-specific microenvironment. We summarized recent literature regarding molecules and pathways and reviewed the effects of CSC biology during the formation of brain metastasis in TNBC. Along with the concept of individualized cancer therapy, certain strategies, namely the patient-derived xenograft model to overcome the lack of treatment-relevant TNBC classification and techniques in BBB disruption to enhance brain efficacy has been proposed in the hope of achieving treatment success.
    Keywords:  brain metastasis; cancer stem cells; triple-negative breast cancer
  22. Cancers (Basel). 2020 Aug 05. pii: E2179. [Epub ahead of print]12(8):
    Giordano C, La Camera G, Gelsomino L, Barone I, Bonofiglio D, Andò S, Catalano S.
      In recent decades, the study of exosome biology has gained growing interest, representing an active area of cancer research with many potential clinical applications. Exosomes are small lipid bilayer particles released by cells with pleiotropic functions that have been reported to regulate the complex intracellular pathway involved in all steps of breast cancer development-from initiation to progression toward a metastatic dissemination. Particularly, the role of these microvesicles has been explored in metastasis, which represents the leading cause of breast cancer morbidity and mortality worldwide. Reports highlight that the plasticity of breast cancer cells, fundamental for the establishment of distant metastasis, may be in part attributed to exosome-carried signals shared between adjacent cells and long-distance cells in the body. In the present review, we will discuss the functions of exosomes in the metastatic breast cancer process and secondary site outgrowth. The possibility to decode the exosome functions in advanced diseases may offer new opportunities for early detection, molecular targeted therapies and exosome-based therapeutics in breast cancer.
    Keywords:  EMT; breast cancer; exosomes; extracellular vesicles; metastasis
  23. Autophagy. 2020 Aug 07.
    Kim S, Cho H, Hong SO, Oh SJ, Lee HJ, Cho E, Woo SR, Song JS, Chung JY, Son SW, Yoon SM, Jeon YM, Jeon S, Yee C, Lee KM, Hewitt SM, Kim JH, Song KH, Kim TW.
      Immune selection drives tumor cells to acquire refractory phenotypes. We previously demonstrated that cytotoxic T lymphocyte (CTL)-mediated immune pressure enriches NANOG+ tumor cells with stem-like and immune-refractory properties that make them resistant to CTLs. Here, we report that the emergence of refractory phenotypes is highly associated with an aberrant macroautophagic/autophagic state of the NANOG+ tumor cells and that the autophagic phenotype arises through transcriptional induction of MAP1LC3B/LC3B by NANOG. Furthermore, we found that upregulation of LC3B expression contributes to an increase in EGF secretion. The subsequent hyperactivation of EGFR-AKT signaling rendered NANOG+ tumor cells resistant to CTL killing. The NANOG-LC3B-p-EGFR axis was preserved across various types of human cancer and correlated negatively with the overall survival of cervical cancer patients. Inhibition of LC3B in immune-refractory tumor models rendered tumors susceptible to adoptive T-cell transfer, as well as PDCD1/PD-1 blockade, and led to successful, long-term control of the disease. Thus, our findings demonstrate a novel link among immune-resistance, stem-like phenotypes, and LC3B-mediated autophagic secretion in immune-refractory tumor cells, and implicate the LC3B-p-EGFR axis as a central molecular target for controlling NANOG+ immune-refractory cancer.
    Keywords:  EGFR; LC3B; MAP1LC3B; NANOG; cancer immunoediting; immune resistance; immunotherapy
  24. Theranostics. 2020 ;10(19): 8494-8512
    Yin H, Wang Y, Wu Y, Zhang X, Zhang X, Liu J, Wang T, Fan J, Sun J, Yang A, Zhang R.
      Enhancer of Zeste Homolog 2 (EZH2), a key epigenetic regulator, is involved in breast cancer progression and metastasis. LOXL4 is increasingly recognized as an important player in cancer progression. To date, how EZH2 regulates LOXL4 in the progression of breast cancer remains unclear. Methods: We evaluated the association between LOX family proteins and EZH2 in invasive breast carcinoma through the starBase v2.0 analysis, and its correlation with breast tumorigenesis using the Oncomine dataset. We then applied miRcode data combined with gene expression omnibus (GEO) data to screen candidate miRNAs mediating the regulation of LOXL4 by EZH2. We explored the regulatory mechanism of EZH2, miR-29b/miR-30d, and LOXL4 in breast cancer cells by qRT-PCR, Western blotting, cell proliferation, colony formation, and wound healing assays, xenograft experiments, dual-luciferase reporter assay, and chromatin immunoprecipitation. All statistical tests were two-sided. Results: Inhibition of EZH2 or LOXL4, or miR-29b/miR-30d overexpression, decreased breast cancer cell proliferation, migration, and metastasis in vitro and in vivo. LOXL4 was identified as a direct target of miR-29b and miR-30d. EZH2 inhibition enhanced miR-30d and miR-29b transcription via promoter binding activity, leading to the reduced expression of LOXL4. Immunohistochemical analysis of human breast cancer specimens and flow cytometry analysis of tumor-infiltrating macrophages in mice showed a positive association of EZH2 with LOXL4 expression and macrophage infiltration. Conclusions: Our findings identified EZH2-miR-29b/miR-30d-LOXL4 signaling pathway was involved in breast tumorigenesis, and suggested that the epigenetic modulation represents a potential therapeutic target for breast cancer by controlling macrophage activation.
    Keywords:  Breast cancer; EZH2; LOXL4; Macrophage; miR-29b/miR-30d
  25. Nat Immunol. 2020 Aug 03.
    Schuijs MJ, Png S, Richard AC, Tsyben A, Hamm G, Stockis J, Garcia C, Pinaud S, Nicholls A, Ros XR, Su J, Eldridge MD, Riedel A, Serrao EM, Rodewald HR, Mack M, Shields JD, Cohen ES, McKenzie ANJ, Goodwin RJA, Brindle KM, Marioni JC, Halim TYF.
      Metastasis constitutes the primary cause of cancer-related deaths, with the lung being a commonly affected organ. We found that activation of lung-resident group 2 innate lymphoid cells (ILC2s) orchestrated suppression of natural killer (NK) cell-mediated innate antitumor immunity, leading to increased lung metastases and mortality. Using multiple models of lung metastasis, we show that interleukin (IL)-33-dependent ILC2 activation in the lung is involved centrally in promoting tumor burden. ILC2-driven innate type 2 inflammation is accompanied by profound local suppression of interferon-γ production and cytotoxic function of lung NK cells. ILC2-dependent suppression of NK cells is elaborated via an innate regulatory mechanism, which is reliant on IL-5-induced lung eosinophilia, ultimately limiting the metabolic fitness of NK cells. Therapeutic targeting of IL-33 or IL-5 reversed NK cell suppression and alleviated cancer burden. Thus, we reveal an important function of IL-33 and ILC2s in promoting tumor metastasis via their capacity to suppress innate type 1 immunity.
  26. Nat Commun. 2020 Aug 04. 11(1): 3883
    Oldrini B, Vaquero-Siguero N, Mu Q, Kroon P, Zhang Y, Galán-Ganga M, Bao Z, Wang Z, Liu H, Sa JK, Zhao J, Kim H, Rodriguez-Perales S, Nam DH, Verhaak RGW, Rabadan R, Jiang T, Wang J, Squatrito M.
      Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.
  27. Int J Cancer. 2020 Aug 05.
    Izraely S, Witz IP.
      The conclusion derived from the information provided in this review is that disseminating tumor cells (DTC) collaborate with the microenvironment of a future metastatic organ site in the establishment of organ-specific metastasis. We review the basic principles of site-specific metastasis and the contribution of the cross talk between DTC and the microenvironment of metastatic sites (metastatic microenvironment - MME) to: the establishment of the organ-specific pre-metastatic niche; the targeted migration of DTC to the endothelium of the future organ-specific metastasis; the transmigration of DTC to this site and the seeding and colonization of DTC in their future MME. We also discuss the role played by DTC-MME interactions on tumor dormancy and on the differential response of tumor cells residing in different MMEs to anti-tumor therapy. Finally, we summarize some studies dealing with the effects of the MME on a unique site-specific metastasis - brain metastasis. This article is protected by copyright. All rights reserved.
    Keywords:  brain metastasis; cancer; metastatic microenvironment; site-specific metastasis
  28. Cancers (Basel). 2020 Jul 29. pii: E2109. [Epub ahead of print]12(8):
    Wood SL, Brown JE.
      Bone metastasis is a major cause of morbidity within solid tumours of the breast, prostate, lung and kidney. Metastasis to the skeleton is associated with a wide range of complications including bone fractures, spinal cord compression, hypercalcaemia and increased bone pain. Improved treatments for bone metastasis, such as the use of anti-bone resorptive bisphosphonate agents, within post-menopausal women have improved disease-free survival; however, these treatments are not without side effects. There is thus a need for biomarkers, which will predict the risk of developing the spread to bone within these cancers. The application of molecular profiling techniques, together with animal model systems and engineered cell-lines has enabled the identification of a series of potential bone-metastasis biomarker molecules predictive of bone metastasis risk. Some of these biomarker candidates have been validated within patient-derived samples providing a step towards clinical utility. Recent developments in multiplex biomarker quantification now enable the simultaneous measurement of up to 96 micro-RNA/protein molecules in a spatially defined manner with single-cell resolution, thus enabling the characterisation of the key molecules active at the sites of pre-metastatic niche formation as well as tumour-stroma signalling. These technologies have considerable potential to inform biomarker discovery. Additionally, a potential future extension of these discoveries could also be the identification of novel drug targets within cancer spread to bone. This chapter summarises recent findings in biomarker discovery within the key bone metastatic cancers (breast, prostate, lung and renal cell carcinoma). Tissue-based and circulating blood-based biomarkers are discussed from the fields of genomics, epigenetic regulation (micro-RNAs) and protein/cell-signalling together with a discussion of the potential future development of these markers towards clinical development.
    Keywords:  biomarkers; bone metastatic cancers; bone microenvironment; micro-RNA; personalised medicine; proteins
  29. Theranostics. 2020 ;10(19): 8573-8590
    Min X, Zhang X, Li Y, Cao X, Cheng H, Li Y, Li C, Kong Q, Mao Q, Peng P, Ni Y, Li J, Duan Y, Liu L, Ding Z.
      Background: Metastasis accounts for 90% of cancer-associated mortality in patients with renal cell carcinoma (RCC). However, the clinical management of RCC metastasis is challenging. Lactate export is known to play an important role in cancer cell migration. This study investigated the role of heat shock protein A12A (HSPA12A) in RCC migration. Methods: HSPA12A expression was examined in 82 pairs of matched RCC tumors and corresponding normal kidney tissues from patients by immunoblotting and immunofluorescence analyses. The proliferation of RCC cells was analyzed using MTT and EdU incorporation assays. The migration of RCC cells was evaluated by wound healing and Transwell migration assays. Extracellular acidification was examined using Seahorse technology. Protein stability was determined following treatment with protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132. Mass spectrometry, immunoprecipitation, and immunoblotting were employed to examine protein-protein interactions. Results: RCC tumors from patients showed downregulation of HSPA12A, which was associated with advanced tumor node metastasis stage. Intriguingly, overexpression of HSPA12A in RCC cells inhibited migration, whereas HSPA12A knockdown had the opposite effect. Lactate export, glycolysis rate, and CD147 protein abundance were also inhibited by HSPA12A overexpression but promoted by HSPA12A knockdown. An interaction of HSPA12A with HRD1 ubiquitin E3 ligase was detected in RCC cells. Further studies demonstrated that CD147 ubiquitination and proteasomal degradation were promoted by HSPA12A overexpression whereas inhibited by HSPA12A knockdown. Notably, the HSPA12A overexpression-induced inhibition of lactate export and migration were abolished by CD147 overexpression. Conclusion: Human RCC shows downregulation of HSPA12A. Overexpression of HSPA12A in RCC cells unstabilizes CD147 through increasing its ubiquitin-proteasome degradation, thereby inhibits lactate export and glycolysis, and ultimately suppresses RCC cell migration. Our results demonstrate that overexpression of HSPA12A might represent a viable strategy for managing RCC metastasis.
    Keywords:  cluster of differentiation 147 (CD147); heat shock protein A12A (HSPA12A); lactate; migration; renal cell carcinoma
  30. Theranostics. 2020 ;10(19): 8721-8743
    Huang T, Song X, Xu D, Tiek D, Goenka A, Wu B, Sastry N, Hu B, Cheng SY.
      Over the past few decades, substantial evidence has convincingly revealed the existence of cancer stem cells (CSCs) as a minor subpopulation in cancers, contributing to an aberrantly high degree of cellular heterogeneity within the tumor. CSCs are functionally defined by their abilities of self-renewal and differentiation, often in response to cues from their microenvironment. Biological phenotypes of CSCs are regulated by the integrated transcriptional, post-transcriptional, metabolic, and epigenetic regulatory networks. CSCs contribute to tumor progression, therapeutic resistance, and disease recurrence through their sustained proliferation, invasion into normal tissue, promotion of angiogenesis, evasion of the immune system, and resistance to conventional anticancer therapies. Therefore, elucidation of the molecular mechanisms that drive cancer stem cell maintenance, plasticity, and therapeutic resistance will enhance our ability to improve the effectiveness of targeted therapies for CSCs. In this review, we highlight the key features and mechanisms that regulate CSC function in tumor initiation, progression, and therapy resistance. We discuss factors for CSC therapeutic resistance, such as quiescence, induction of epithelial-to-mesenchymal transition (EMT), and resistance to DNA damage-induced cell death. We evaluate therapeutic approaches for eliminating therapy-resistant CSC subpopulations, including anticancer drugs that target key CSC signaling pathways and cell surface markers, viral therapies, the awakening of quiescent CSCs, and immunotherapy. We also assess the impact of new technologies, such as single-cell sequencing and CRISPR-Cas9 screening, on the investigation of the biological properties of CSCs. Moreover, challenges remain to be addressed in the coming years, including experimental approaches for investigating CSCs and obstacles in therapeutic targeting of CSCs.
    Keywords:  CSC-targeting therapies; cancer stem cells; epigenetics; metabolism; therapy resistance; transcriptional and posttranslational regulation; tumor microenvironment