bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒11‒22
27 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. FEBS J. 2020 Nov 15.
    Damen MPF, van Rheenen J, Scheele CLGJ.
      Over the years, developments in oncology led to significantly improved clinical outcome for cancer patients. However, cancer recurrence after initial treatment response still poses a major challenge, as it often involves more aggressive, metastatic disease. The presence of dormant cancer cells is associated with recurrence, metastasis and poor clinical outcome, suggesting that these cells may play a crucial role in the process of disease relapse. Cancer cell dormancy typically presents as growth arrest while retaining proliferative capacity and can be induced or reversed by a wide array of cell-intrinsic and extrinsic factors. Conventional therapies preferentially target fast dividing cells, leaving dormant cancer cells largely insensitive to these treatments. In this review, we discuss the role of dormant cancer cells in cancer recurrence and highlight how novel therapy strategies based on cell cycle modulation, modifications of existing drugs or enhanced drug delivery vehicles may be used to specifically target this subpopulation of tumor cells, and thereby have the potential to prevent disease recurrence.
    Keywords:  Cancer recurrence; Cell cycle modulation; Dormancy-targeting drugs; Dormant cancer cells; Enhanced drug delivery; Therapy resistance
    DOI:  https://doi.org/10.1111/febs.15626
  2. Cancer Cell. 2020 Nov 18. pii: S1535-6108(20)30541-9. [Epub ahead of print]
    Bhatt S, Pioso MS, Olesinski EA, Yilma B, Ryan JA, Mashaka T, Leutz B, Adamia S, Zhu H, Kuang Y, Mogili A, Louissaint AJ, Bohl SR, Kim AS, Mehta AK, Sanghavi S, Wang Y, Morris E, Halilovic E, Paweletz CP, Weinstock DM, Garcia JS, Letai A.
      Acquired resistance to BH3 mimetic antagonists of BCL-2 and MCL-1 is an important clinical problem. Using acute myelogenous leukemia (AML) patient-derived xenograft (PDX) models of acquired resistance to BCL-2 (venetoclax) and MCL-1 (S63845) antagonists, we identify common principles of resistance and persistent vulnerabilities to overcome resistance. BH3 mimetic resistance is characterized by decreased mitochondrial apoptotic priming as measured by BH3 profiling, both in PDX models and human clinical samples, due to alterations in BCL-2 family proteins that vary among cases, but not to acquired mutations in leukemia genes. BCL-2 inhibition drives sequestered pro-apoptotic proteins to MCL-1 and vice versa, explaining why in vivo combinations of BCL-2 and MCL-1 antagonists are more effective when concurrent rather than sequential. Finally, drug-induced mitochondrial priming measured by dynamic BH3 profiling (DBP) identifies drugs that are persistently active in BH3 mimetic-resistant myeloblasts, including FLT-3 inhibitors and SMAC mimetics.
    Keywords:  BCL-2; BH3 mimetics; BH3 profiling; FLT-3; MCL-1; SMAC; leukemia; mitochondria; precision cancer medicine; venetoclax
    DOI:  https://doi.org/10.1016/j.ccell.2020.10.010
  3. Proc Natl Acad Sci U S A. 2020 Nov 17. pii: 202009506. [Epub ahead of print]
    Replogle JM, Zhou W, Amaro AE, McFarland JM, Villalobos-Ortiz M, Ryan J, Letai A, Yilmaz O, Sheltzer J, Lippard SJ, Ben-David U, Amon A.
      Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress and cell cycle delays, foremost in G1 and S phase. Here, we investigate how aneuploidy causes both slow proliferation and poor disease outcome. We test the hypothesis that aneuploidy brings about resistance to chemotherapies because of a general feature of the aneuploid condition-G1 delays. We show that single chromosome gains lead to increased resistance to the frontline chemotherapeutics cisplatin and paclitaxel. Furthermore, G1 cell cycle delays are sufficient to increase chemotherapeutic resistance in euploid cells. Mechanistically, G1 delays increase drug resistance to cisplatin and paclitaxel by reducing their ability to damage DNA and microtubules, respectively. Finally, we show that our findings are clinically relevant. Aneuploidy correlates with slowed proliferation and drug resistance in the Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude that a general and seemingly detrimental effect of aneuploidy, slowed proliferation, provides a selective benefit to cancer cells during chemotherapy treatment.
    Keywords:  aneuploidy; cell cycle; chemotherapy resistance; cisplatin; paclitaxel
    DOI:  https://doi.org/10.1073/pnas.2009506117
  4. Clin Cancer Res. 2020 Nov 18. pii: clincanres.3316.2020. [Epub ahead of print]
    Börcsök J, Sztupinszki Z, Bekele R, Gao SP, Diossy M, Samant AS, Dillon KM, Tisza V, Spisák S, Rusz O, Csabai I, Pappot H, Frazier ZJ, Konieczkowski DJ, Liu D, Vasani N, Rodrigues JA, Solit DB, Hoffman-Censits JH, Plimack ER, Rosenberg JE, Lazaro JB, Taplin ME, Iyer G, Brunak S, Lozsa R, Van Allen EM, Szüts D, Mouw KW, Szallasi Z.
      PURPOSE: Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2 mutant cases.EXPERIMENTAL DESIGN: We use a series of NER proficient and NER deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anti-cancer agent. In addition, we use available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity.
    RESULTS: We identify a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also find that a composite mutational signature of ERCC2 deficiency is strongly associated with cisplatin response in patients and is also associated with cisplatin and irofulven sensitivity in preclinical models.
    CONCLUSIONS: Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anti-cancer agent with minimal activity in NER proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents including cisplatin and irofulven.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-3316
  5. Nat Commun. 2020 11 17. 11(1): 5865
    Pietrobono S, Anichini G, Sala C, Manetti F, Almada LL, Pepe S, Carr RM, Paradise BD, Sarkaria JN, Davila JI, Tofani L, Battisti I, Arrigoni G, Ying L, Zhang C, Li H, Meves A, Fernandez-Zapico ME, Stecca B.
      Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.
    DOI:  https://doi.org/10.1038/s41467-020-19575-2
  6. Oncogene. 2020 Nov 20.
    Buckup M, Rice MA, Hsu EC, Garcia-Marques F, Liu S, Aslan M, Bermudez A, Huang J, Pitteri SJ, Stoyanova T.
      Prostate cancer is responsible for over 30,000 US deaths annually, attributed largely to incurable metastatic disease. Here, we demonstrate that high levels of plectin are associated with localized and metastatic human prostate cancer when compared to benign prostate tissues. Knock-down of plectin inhibits prostate cancer cell growth and colony formation in vitro, and growth of prostate cancer xenografts in vivo. Plectin knock-down further impairs aggressive and invasive cellular behavior assessed by migration, invasion, and wound healing in vitro. Consistently, plectin knock-down cells have impaired metastatic colonization to distant sites including liver, lung, kidney, bone, and genitourinary system. Plectin knock-down inhibited number of metastases per organ, as well as decreased overall metastatic burden. To gain insights into the role of plectin in prostate cancer growth and metastasis, we performed proteomic analysis of prostate cancer plectin knock-down xenograft tissues. Gene set enrichment analysis shows an increase in levels of proteins involved with extracellular matrix and laminin interactions, and a decrease in levels of proteins regulating amino acid metabolism, cytoskeletal proteins, and cellular response to stress. Collectively these findings demonstrate that plectin is an important regulator of prostate cancer cell growth and metastasis.
    DOI:  https://doi.org/10.1038/s41388-020-01557-9
  7. Nat Commun. 2020 Nov 20. 11(1): 5911
    Okazaki K, Anzawa H, Liu Z, Ota N, Kitamura H, Onodera Y, Alam MM, Matsumaru D, Suzuki T, Katsuoka F, Tadaka S, Motoike I, Watanabe M, Hayasaka K, Sakurada A, Okada Y, Yamamoto M, Suzuki T, Kinoshita K, Sekine H, Motohashi H.
      Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.
    DOI:  https://doi.org/10.1038/s41467-020-19593-0
  8. Oncogene. 2020 Nov 18.
    Han A, Purwin TJ, Bechtel N, Liao C, Chua V, Seifert E, Sato T, Schug ZT, Speicher DW, William Harbour J, Aplin AE.
      Cancer cell metabolism is a targetable vulnerability; however, a precise understanding of metabolic heterogeneity is required. Inactivating mutations in BRCA1-associated protein 1 (BAP1) are associated with metastasis in uveal melanoma (UM), the deadliest adult eye cancer. BAP1 functions in UM remain unclear. UM patient sample analysis divided BAP1 mutant UM tumors into two subgroups based on oxidative phosphorylation (OXPHOS) gene expression suggesting metabolic heterogeneity. Consistent with patient data, transcriptomic analysis of BAP1 mutant UM cell lines also showed OXPHOShigh or OXPHOSlow subgroups. Integrated RNA sequencing, metabolomics, and molecular analyses showed that OXPHOShigh BAP1 mutant UM cells utilize glycolytic and nucleotide biosynthesis pathways, whereas OXPHOSlow BAP1 mutant UM cells employ fatty acid oxidation. Furthermore, the two subgroups responded to different classes of metabolic suppressors. Our findings indicate that targeting cancer metabolism is a promising therapeutic option for BAP1 mutant UM; however, tailored approaches may be required due to metabolic heterogeneities.
    DOI:  https://doi.org/10.1038/s41388-020-01554-y
  9. Nat Commun. 2020 11 16. 11(1): 5799
    Naffar-Abu Amara S, Kuiken HJ, Selfors LM, Butler T, Leung ML, Leung CT, Kuhn EP, Kolarova T, Hage C, Ganesh K, Panayiotou R, Foster R, Rueda BR, Aktipis A, Spellman P, Ince TA, Xiu J, Oberley M, Gatalica Z, Navin N, Mills GB, Bronson RT, Brugge JS.
      The extent and importance of functional heterogeneity and crosstalk between tumor cells is poorly understood. Here, we describe the generation of clonal populations from a patient-derived ovarian clear cell carcinoma model which forms malignant ascites and solid peritoneal tumors upon intraperitoneal transplantation in mice. The clonal populations are engineered with secreted Gaussia luciferase to monitor tumor growth dynamics and tagged with a unique DNA barcode to track their fate in multiclonal mixtures during tumor progression. Only one clone, CL31, grows robustly, generating exclusively malignant ascites. However, multiclonal mixtures form large solid peritoneal metastases, populated almost entirely by CL31, suggesting that transient cooperative interclonal interactions are sufficient to promote metastasis of CL31. CL31 uniquely harbors ERBB2 amplification, and its acquired metastatic activity in clonal mixtures is dependent on transient exposure to amphiregulin, which is exclusively secreted by non-tumorigenic clones. Amphiregulin enhances CL31 mesothelial clearance, a prerequisite for metastasis. These findings demonstrate that transient, ostensibly innocuous tumor subpopulations can promote metastases via "hit-and-run" commensal interactions.
    DOI:  https://doi.org/10.1038/s41467-020-19584-1
  10. BMC Med. 2020 Nov 19. 18(1): 349
    Charmsaz S, Doherty B, Cocchiglia S, Varešlija D, Marino A, Cosgrove N, Marques R, Priedigkeit N, Purcell S, Bane F, Bolger J, Byrne C, O'Halloran PJ, Brett F, Sheehan K, Brennan K, Hopkins AM, Keelan S, Jagust P, Madden S, Martinelli C, Battaglini M, Oesterreich S, Lee AV, Ciofani G, Hill ADK, Young LS.
      BACKGROUND: Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood-brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets.METHODS: Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target's natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis.
    RESULTS: Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis.
    CONCLUSION: ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.
    Keywords:  ADAM22; Blood–brain barrier; Brain metastases; Breast cancer metastases; ECM signalling; LGI1; Targeted therapy
    DOI:  https://doi.org/10.1186/s12916-020-01806-4
  11. Cancers (Basel). 2020 Nov 13. pii: E3366. [Epub ahead of print]12(11):
    Aladowicz E, Granieri L, Marocchi F, Punzi S, Giardina G, Ferrucci PF, Mazzarol G, Capra M, Viale G, Confalonieri S, Gandini S, Lotti F, Lanfrancone L.
      Metastases are the primary cause of cancer-related deaths. The underlying molecular and biological mechanisms remain, however, elusive, thus preventing the design of specific therapies. In melanomas, the metastatic process is influenced by the acquisition of metastasis-associated mutational and epigenetic traits and the activation of metastatic-specific signaling pathways in the primary melanoma. In the current study, we investigated the role of an adaptor protein of the Shc family (ShcD) in the acquisition of metastatic properties by melanoma cells, exploiting our cohort of patient-derived xenografts (PDXs). We provide evidence that the depletion of ShcD expression increases a spread cell shape and the capability of melanoma cells to attach to the extracellular matrix while its overexpression switches their morphology from elongated to rounded on 3D matrices, enhances cells' invasive phenotype, as observed on collagen gel, and favors metastasis formation in vivo. ShcD overexpression sustains amoeboid movement in melanoma cells, by suppressing the Rac1 signaling pathway through the confinement of DOCK4 in the cytoplasm. Inactivation of the ShcD signaling pathway makes melanoma cells more sensitive to therapeutic treatments. Consistently, ShcD expression predicts poor outcome in a cohort of 183 primary melanoma patients.
    Keywords:  DOCK4; Rac1; ShcD adaptor protein; amoeboid motility; melanoma PDX; melanoma metastasis
    DOI:  https://doi.org/10.3390/cancers12113366
  12. Cancers (Basel). 2020 Nov 16. pii: E3385. [Epub ahead of print]12(11):
    Schaller J, Agudo J.
      Cancer immunotherapy has shifted the paradigm in cancer therapy by revitalizing immune responses against tumor cells. Specifically, in primary tumors cancer cells evolve in an immunosuppressive microenvironment, which protects them from immune attack. However, during tumor progression, some cancer cells leave the protective tumor mass, disseminating and seeding secondary organs. These initial disseminated tumor cells (DTCs) should potentially be susceptible to recognition by the immune system in the new host tissues. Although Natural Killer or T cells eliminate some of these DTCs, a fraction escape anti-tumor immunity and survive, thus giving rise to metastatic colonization. How DTCs interact with immune cells and the underpinnings that regulate imperfect immune responses during tumor dissemination remain poorly understood. Uncovering such mechanisms of immune evasion may contribute to the development of immunotherapy specifically targeting DTCs. Here we review current knowledge about systemic and site-specific immune-cancer crosstalk in the early steps of metastasis formation. Moreover, we highlight how conventional cancer therapies can shape the pre-metastatic niche enabling immune escape of newly arrived DTCs.
    Keywords:  anti-tumor immunity; cytotoxic T cell; dendritic cell; disseminated tumor cell; immune evasion; immune surveillance; metastasis-initiating cell; myeloid cell; natural killer cell
    DOI:  https://doi.org/10.3390/cancers12113385
  13. Nat Commun. 2020 11 18. 11(1): 5878
    Bao Y, Oguz G, Lee WC, Lee PL, Ghosh K, Li J, Wang P, Lobie PE, Ehmsen S, Ditzel HJ, Wong A, Tan EY, Lee SC, Yu Q.
      HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors.
    DOI:  https://doi.org/10.1038/s41467-020-19704-x
  14. Front Immunol. 2020 ;11 2166
    Sistigu A, Musella M, Galassi C, Vitale I, De Maria R.
      Cancer cell dormancy is a common feature of human tumors and represents a major clinical barrier to the long-term efficacy of anticancer therapies. Dormant cancer cells, either in primary tumors or disseminated in secondary organs, may reawaken and relapse into a more aggressive disease. The mechanisms underpinning dormancy entry and exit strongly resemble those governing cancer cell stemness and include intrinsic and contextual cues. Cellular and molecular components of the tumor microenvironment persistently interact with cancer cells. This dialog is highly dynamic, as it evolves over time and space, strongly cooperates with intrinsic cell nets, and governs cancer cell features (like quiescence and stemness) and fate (survival and outgrowth). Therefore, there is a need for deeper insight into the biology of dormant cancer (stem) cells and the mechanisms regulating the equilibrium quiescence-versus-proliferation are vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. Here, we review and discuss microenvironmental regulations of cancer dormancy and its parallels with cancer stemness, and offer insights into the therapeutic strategies adopted to prevent a lethal recurrence, by either eradicating resident dormant cancer (stem) cells or maintaining them in a dormant state.
    Keywords:  cancer stem cells (CSC); disseminated cancer cells (DCC); dormancy; immune escape; immunoediting of cancer; reawakening; tumor evolution; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2020.02166
  15. Proc Natl Acad Sci U S A. 2020 Nov 16. pii: 201920240. [Epub ahead of print]
    Grbovic-Huezo O, Pitter KL, Lecomte N, Saglimbeni J, Askan G, Holm M, Melchor JP, Chandwani R, Joshi S, Haglund C, Iacobuzio-Donahue CA, Chiosis G, Tammela T, Leach SD.
      Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, which limits surgical options and portends a dismal prognosis. Current oncologic PDAC therapies confer marginal benefit and, thus, a significant unmet clinical need exists for new therapeutic strategies. To identify effective PDAC therapies, we leveraged a syngeneic orthotopic PDAC transplant mouse model to perform a large-scale, in vivo screen of 16 single-agent and 41 two-drug targeted therapy combinations in mice. Among 57 drug conditions screened, combined inhibition of heat shock protein (Hsp)-90 and MEK was found to produce robust suppression of tumor growth, leading to an 80% increase in the survival of PDAC-bearing mice with no significant toxicity. Mechanistically, we observed that single-agent MEK inhibition led to compensatory activation of resistance pathways, including components of the PI3K/AKT/mTOR signaling axis, which was overcome with the addition of HSP90 inhibition. The combination of HSP90(i) + MEK(i) was also active in vitro in established human PDAC cell lines and in vivo in patient-derived organoid PDAC transplant models. These findings encourage the clinical development of HSP90(i) + MEK(i) combination therapy and highlight the power of clinically relevant in vivo model systems for identifying cancer therapies.
    Keywords:  HSP90; MEK; PDAC; pancreatic cancer; trametinib
    DOI:  https://doi.org/10.1073/pnas.1920240117
  16. Cancer Res. 2020 Nov 17. pii: canres.1517.2020. [Epub ahead of print]
    Sun L, Yang X, Huang X, Yao Y, Wei X, Yang S, Zhou D, Zhang W, Long Z, Xu X, Zhu X, He S, Su X.
      Alteration in lipid composition is an important metabolic adaptation by cancer cells to support tumorigenesis and metastasis. Fatty acid 2-hydroxylase (FA2H) introduces a chiral hydroxyl group at the second carbon of FA backbones and influences lipid structures and metabolic signaling. However, the underlying mechanisms through which FA 2-hydroxylation is coupled to metabolic adaptation and tumor growth remain elusive. Here we show that FA2H regulates specific metabolic reprogramming and oncogenic signaling in the development of colorectal cancer (CRC). FA2H was highly expressed in normal colorectal tissues. Assessments through deciphering both published high-throughput data and curated human CRC samples revealed significant suppression of FA2H in tumors, which is correlated with unfavorable prognosis. Experiments with multiple models of genetic manipulation or treatment with an enzymatic product of FA2H, (R)-2-hydroxy palmitic acid ((R)-2-OHPA), demonstrated that FA 2-hydroxylation inhibits CRC cell proliferation, migration, epithelial-mesenchymal transition (EMT) progression and tumor growth. Bioinformatics analysis suggested that FA2H functions through AMP-activated protein kinase/Yes-associated protein (AMPK/YAP) pathway, which was confirmed in CRC cells as well as in tumors. Lipidomics analysis revealed an accumulation of polyunsaturated fatty acids (PUFA) in cells with FA2H overexpression, which may contribute to the observed nutrient deficiency and AMPK activation. Collectively, these data demonstrate that FA 2-hydroxylation initiates a metabolic signaling cascade to suppress colorectal tumor growth and metastasis via the YAP transcriptional axis and provides a strategy to improve CRC treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1517
  17. Cancer Res. 2020 Nov 17. pii: canres.1992.2020. [Epub ahead of print]
    Wang J, Pollard K, Calizo A, Pratilas CA.
      Malignant peripheral nerve sheath tumors often arise in patients with neurofibromatosis type 1 and are among the most treatment-refractory types of sarcoma. Overall survival in patients with relapsed disease remains poor, and thus novel therapeutic approaches are needed. NF1 is essential for negative regulation of RAS activity and is altered in about 90% of MPNST. A complex interplay of upstream signaling and parallel RAS-driven pathways characterizes NF1-driven tumorigenesis, and inhibiting more than one RAS effector pathway is therefore necessary. To devise potential combination therapeutic strategies, we identified actionable alterations in signaling that underlie adaptive and acquired resistance to MEK inhibitor (MEKi). Using a series of proteomic, biochemical, and genetic approaches in an in vitro model of MEKi resistance provided a rationale for combination therapies. HGF/MET signaling was elevated in the MEKi-resistant model. HGF overexpression conferred resistance to MEKi in parental cells. Depletion of HGF or MET restored sensitivity of MEKi-resistant cells to MEKi. Finally, a combination of MEK and MET inhibition demonstrated activity in models of MPNST and may therefore be effective in patients with MPNST harboring genetic alterations in NF1.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1992
  18. Oncogene. 2020 Nov 20.
    Hu Z, Wang X, Li D, Cao L, Cui H, Xu G.
      The key component in the UFM1 conjugation system, UFM1-binding and PCI domain-containing protein 1 (UFBP1), regulates many biological processes. Recently it has been shown that low UFBP1 protein level is associated with the worse outcome of gastric cancer patients. However, how it responses to the sensitivity of gastric cancer to chemotherapy drugs and the underlying molecular mechanism remain elusive. Here, we discovered that high UFBP1 expression increases the progression-free survival of advanced gastric cancer patients treated with platinum-based chemotherapy. Cell-line based studies unveiled that UFBP1 expression enhances while UFBP1 knockdown attenuates the sensitivity of gastric cancer cells to cisplatin. High-throughput SILAC-based quantitative proteomic analysis revealed that the protein level of aldo-keto reductase 1Cs (AKR1Cs) is significantly downregulated by UFBP1. Flow cytometry analysis showed that UFBP1 expression increases while UFBP1 knockdown reduces reactive oxygen species upon cisplatin treatment. We further disclosed that UFBP1 attenuates the gene expression of AKR1Cs and the transcription activity of the master oxidative stress-response transcription factor Nrf2 (nuclear factor erythroid-2-related factor 2). Detailed mechanistic studies manifested that UFBP1 promotes the formation of K48-linked polyubiquitin chains on Nrf2 and thus augments its proteasome-mediated degradation. Experiments using genetic depletion and pharmacological activation in vitro and in vivo demonstrated that UFBP1 enhances the sensitivity of gastric cancer cells to cisplatin through the Nrf2/AKR1C axis. Overall, this work discovered a novel prognostic biomarker for gastric cancer patients treated with platinum-based chemotherapy and elucidated the underlying molecular mechanism, which may benefit to future personalized chemotherapy.
    DOI:  https://doi.org/10.1038/s41388-020-01551-1
  19. Cancer Discov. 2020 Nov 20. pii: CD-20-0766. [Epub ahead of print]
    Silverman IM, Hollebecque A, Friboulet L, Owens S, Newton RC, Zhen H, Feliz L, Zecchetto C, Melisi D, Burn TC.
      Pemigatinib, a selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor, has demonstrated antitumor activity in FIGHT-202, a phase 2 study in patients with cholangiocarcinoma harboring FGFR2 fusions/rearrangements, and has gained regulatory approval in the United States. Eligibility for FIGHT-202 was assessed using genomic profiling; here, these data were utilized to characterize the genomic landscape of cholangiocarcinoma, and to uncover unique molecular features of patients harboring FGFR2 rearrangements. The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with FGFR2. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Genomic subsets of patients with other potentially actionable FGF/FGFR alterations were also identified. Our study provides a framework for molecularly-guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0766
  20. Mol Cancer. 2020 Nov 20. 19(1): 161
    Park JM, Kim YJ, Park S, Park M, Farrand L, Nguyen CT, Ann J, Nam G, Park HJ, Lee J, Kim JY, Seo JH.
      Trastuzumab resistance in HER2-positive breast cancer is associated with a poorer prognosis. HSP90 is thought to play a major role in such resistance, but N-terminal inhibitors of this target have had little success. We sought to investigate the utility of NCT-547, a novel, rationally-designed C-terminal HSP90 inhibitor in the context of overcoming trastuzumab resistance. NCT-547 treatment significantly induced apoptosis without triggering the heat shock response (HSR), accompanied by caspase-3/- 7 activation in both trastuzumab-sensitive and -resistant cells. NCT-547 effectively promoted the degradation of full-length HER2 and truncated p95HER2, while also attenuating hetero-dimerization of HER2 family members. The impairment of cancer stem-like traits was observed with reductions in ALDH1 activity, the CD24low/CD44high subpopulation, and mammosphere formation in vitro and in vivo. NCT-547 was an effective inhibitor of tumor growth and angiogenesis, and no toxic outcomes were found in initial hepatic and renal analysis. Our findings suggest that NCT-547 may have applications in addressing trastuzumab resistance in HER2-positive breast cancer.
    Keywords:  C-terminal HSP90 inhibitor; Cancer stem cells; HER2; HER2-positive breast cancer; NCT-547; Trastuzumab resistance; p95HER2
    DOI:  https://doi.org/10.1186/s12943-020-01283-6
  21. Cancers (Basel). 2020 Nov 12. pii: E3350. [Epub ahead of print]12(11):
    Balestrino R, Rudà R, Soffietti R.
      Brain metastases (BMs) are the most common intracranial tumours in adults and occur up to 3-10 times more frequently than primary brain tumours. BMs may be the cause of the neurological presenting symptoms in patients with otherwise previously undiagnosed cancer. In up to 15% of patients with BMs, the primary tumour cannot be identified. These cases are known as BM of cancer of unknown primary (CUP) (BM-CUP). CUP has an early and aggressive metastatic spread, poor response to chemotherapy, and poor prognosis. The pathogenesis of CUP seems to be characterized by a specific underlying pro-metastatic signature. The understanding of BM-CUP, despite its relative frequency and unfavourable outcome, is still incomplete and clear indications on management are missing. Advances in diagnostic tools, molecular characterization, and target therapy have shifted the paradigm in the approach to metastasis from CUP: while earlier studies stressed the importance of finding the primary tumour and deciding on treatment based on the primary diagnosis, most recent studies focus on the importance of identifying targetable molecular markers in the metastasis itself. The aim of this review is to summarize current evidence on BM-CUP, from the diagnosis and pathogenesis to the treatment, with a focus on available studies and ongoing clinical trials.
    Keywords:  brain metastasis; cancer of unknown primary; clinical trial; gene expression profiling; molecular markers; neuro-oncology; target therapy
    DOI:  https://doi.org/10.3390/cancers12113350
  22. Cancers (Basel). 2020 Nov 13. pii: E3368. [Epub ahead of print]12(11):
    Fattore L, Mancini R, Ciliberto G.
      Cancer stem cells (CSCs) have historically been defined as slow cycling elements that are able to differentiate into mature cells but without dedifferentiation in the opposite direction. Thanks to advances in genomic and non-genomic technologies, the CSC theory has more recently been reconsidered in a dynamic manner according to a "phenotype switching" plastic model. Transcriptional reprogramming rewires this plasticity and enables heterogeneous tumors to influence cancer progression and to adapt themselves to drug exposure by selecting a subpopulation of slow cycling cells, similar in nature to the originally defined CSCs. This model has been conceptualized for malignant melanoma tailored to explain resistance to target therapies. Here, we conducted a bioinformatics analysis of available data directed to the identification of the molecular pathways sustaining slow cycling melanoma stem cells. Using this approach, we identified a signature of 25 genes that were assigned to four major clusters, namely 1) kinases and metabolic changes, 2) melanoma-associated proteins, 3) Hippo pathway and 4) slow cycling/CSCs factors. Furthermore, we show how a protein-protein interaction network may be the main driver of these melanoma cell subpopulations. Finally, mining The Cancer Genome Atlas (TCGA) data we evaluated the expression levels of this signature in the four melanoma mutational subtypes. The concomitant alteration of these genes correlates with the worst overall survival (OS) for melanoma patients harboring BRAF-mutations. All together these results underscore the potentiality to target this signature to selectively kill CSCs and to achieve disease control in melanoma.
    Keywords:  OXPHOS; cancer stem cells; drug resistance; lipid metabolism; melanoma; slow cycling phenotype; target therapy
    DOI:  https://doi.org/10.3390/cancers12113368
  23. Nat Rev Cancer. 2020 Nov 19.
    Chen X, Cubillos-Ruiz JR.
      Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours.
    DOI:  https://doi.org/10.1038/s41568-020-00312-2
  24. Theranostics. 2020 ;10(26): 12060-12071
    Zhang Q, Rong Y, Yi K, Huang L, Chen M, Wang F.
      Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors and metastatic lesions and provide significant information about tumor progression and metastasis. CTCs contribute to tumor metastasis through the epithelial-to-mesenchymal transition (EMT). CTC clusters and stem-like phenotypes lead to a more aggressive and metastatic potential. CTCs retain the heterogeneity and imitate the nature of corresponding primary tumors. Therefore, it is important to use single-cell based analysis to obtain information on tumor heterogeneity and biology. CTCs are also good candidates for building preclinical models (especially 3D organoid cultures) for drug screening, disease modeling, genome editing, tumor immunity research, and organ-like biobank establishment. In this article, we summarize the current CTC capture technology, dissect the phenotypes associated with CTC metastasis, and review the progress in single-cell based analysis and preclinical modeling of the pattern and kinetics of CTCs. In particular, we discuss the use of CTCs to assess the progression of hepatocellular carcinoma (HCC).
    Keywords:  circulating tumor cells; clinical application; hepatocellular carcinoma; preclinical models; single-cell based analysis
    DOI:  https://doi.org/10.7150/thno.48918
  25. Clin Cancer Res. 2020 Nov 17. pii: clincanres.3683.2018. [Epub ahead of print]
    Testa JR, Tan Y, Sementino E, Cheung M, Peri S, Menges CW, Kukuyan AM, Zhang T, Khazak V, Fox LA, Ross EA, Ramanathan S, Jhanwar SC, Flores RM, Balachandran S.
      PURPOSE: Receptor-interacting protein kinase RIPK3 phosphorylates effector molecule MLKL to trigger necroptosis. Although RIPK3 loss is seen in several human cancers, its role in malignant mesothelioma (MM) is unknown. This study aimed to determine if RIPK3 functions as a potential tumor suppressor to limit development of MM.EXPERIMENTAL DESIGN: RIPK3 expression was examined in 66 MM tumors and cell lines. Promoter methylation and DNMT1 siRNAstudies were performed to assess the mode of RIPK3 silencing in RIPK3-deficient MM cells. Restoration of RIPK3 expression in RIPK3-negative MM cells, either by treatment with 5-aza-2'-deoxycytidine or lentiviral expression of cDNA, was performed to assess effects on cell viability, necrosis, and chemosensitization.
    RESULTS: Loss of RIPK3 expression was observed in 42/66 (63%) primary MMs and MM cell lines, and RT-PCR analysis demonstrated that downregulation occurs at the transcriptional level, consistent with epigenetic silencing. RIPK3-negative MM cells treated with 5-aza-2'-deoxycytidine resulted in re-expression of RIPK3 and chemosensitization. Ectopic expression of RIPK3 also resulted in chemosensitization and led to necroptosis, the latter demonstrated by phosphorylation of downstream target MLKL and confirmed by rescue experiments. Mining of RIPK3 expression and survival outcomes among MM patients available from The Cancer Genome Atlas repository revealed that promoter methylation of RIPK3 is associated with reduced RIPK3 expression and poor prognosis.
    CONCLUSIONS: These data suggest that RIPK3 acts as a tumor suppressor in MM by triggering necroptosis and that epigenetic silencing of RIPK3 by DNA methylation impairs necroptosis and contributes to chemoresistance and poor survival in this incurable disease.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-18-3683
  26. Mol Cancer Res. 2020 Nov 18. pii: molcanres.0289.2020. [Epub ahead of print]
    Lee D, Lee DY, Hwang YS, Seo HR, Lee SA, Kwon J.
      Many chemotherapeutic drugs produce double-strand breaks (DSBs) on cancer cell DNA, thereby inducing cell death. However, the DNA damage response (DDR) enables cancer cells to overcome DNA damage and escape cell death, often leading to therapeutic resistance and unsuccessful outcomes. It is therefore important to develop inhibitors that target DDR proteins to render cancer cells hypersensitive to DNA damage. Here, we investigated the applicability of PFI-3, a recently developed bromodomain (BRD) inhibitor specifically targeting the SWI/SNF chromatin remodeler that functions to promote DSB repair, in cancer treatment. We verified that PFI-3 effectively blocks chromatin binding of its target BRDs and dissociates the corresponding SWI/SNF proteins from chromatin. We then found that, while having little toxicity as a single agent, PFI-3 synergistically sensitizes several human cancer cell lines to DNA damage induced by chemotherapeutic drugs such as doxorubicin. This PFI-3 activity occurs only for the cancer cells that require SWI/SNF for DNA repair. Our mechanism studies show that PFI-3 exerts the DNA damage-sensitizing effect by directly blocking SWI/SNF's chromatin binding, which leads to defects in DSB repair and aberrations in damage checkpoints, eventually resulting in increase of cell death primarily via necrosis and senescence. This work therefore demonstrates the activity of PFI-3 to sensitize cancer cells to DNA damage and its mechanism of action via SWI/SNF targeting, providing an experimental rationale for developing PFI-3 as a sensitizing agent in cancer chemotherapy. Implications: This study, revealing the activity of PFI-3 to sensitize cancer cells to chemotherapeutic drugs, provides an experimental rationale for developing this BRD inhibitor as a sensitizing agent in cancer chemotherapy.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0289
  27. Front Oncol. 2020 ;10 586069
    Alvarez-Meythaler JG, Garcia-Mayea Y, Mir C, Kondoh H, LLeonart ME.
      Cancer remains one of the leading causes of death worldwide, despite significant advances in cancer research and improvements in anticancer therapies. One of the major obstacles to curing cancer is the difficulty of achieving the complete annihilation of resistant cancer cells. The resistance of cancer cells may not only be due to intrinsic factors or factors acquired during the evolution of the tumor but may also be caused by chemotherapeutic treatment failure. Conversely, autophagy is a conserved cellular process in which intracellular components, such as damaged organelles, aggregated or misfolded proteins and macromolecules, are degraded or recycled to maintain cellular homeostasis. Importantly, autophagy is an essential mechanism that plays a key role in tumor initiation and progression. Depending on the cellular context and microenvironmental conditions, autophagy acts as a double-edged sword, playing a role in inducing apoptosis or promoting cell survival. In this review, we propose several scenarios in which autophagy could contribute to cell survival or cell death. Moreover, a special focus on novel promising targets and therapeutic strategies based on autophagic resistant cells is presented.
    Keywords:  autophagy; cancer; protective autophagy; resistance; therapy
    DOI:  https://doi.org/10.3389/fonc.2020.586069