bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒08‒23
thirty papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Clin Cancer Res. 2020 Aug 20. pii: clincanres.2773.2019. [Epub ahead of print]
    Marusak C, Thakur V, Li Y, Freitas JT, Zmina P, Chang M, Gao M, Tan J, Xiao M, Lu Y, Mills GB, Flaherty K, Frederick DT, Miao B, Sullivan RJ, Moll T, Boland GM, Herlyn M, Zhang G, Bedogni B, Thakur VS.
      PURPOSE: The extracellular matrix (ECM) is an intriguing yet understudied component of therapy resistance. Here we investigated the role of ECM remodeling by the collagenase MT1-MMP in conferring resistance of BRAF-mutant melanoma to BRAF inhibitor therapy.EXPERIMENTAL DESIGN: Publicly available RNA sequencing (RNAseq) data and reverse-phase-protein-array (RPPA) were used to determine the relevance of MT1-MMP up-regulation in BRAFi-resistant melanoma in patients, PDX and cell line derived tumors. shRNA-mediated knockdown of MT1-MMP; inhibition via the selective MT1-MMP/MMP2 inhibitor, ND322; or overexpression of MT1-MMP were used to assess the role of MT1-MMP in mediating resistance to BRAFi.
    RESULTS: MT1-MMP was consistently up-regulated in post-treatment tumor samples derived from patients upon disease progression and melanoma xenografts and cell lines that acquired resistance to BRAFi. shRNA or ND322 mediated inhibition of MT1-MMP synergized with BRAFi leading to re-sensitization of resistant cells and tumors to BRAFi. Resistance depends on the ability of cells to cleave the ECM. Resistant cells seeded in MT1-MMP un-cleavable matrixes were re-sensitized to BRAFi similarly to MT1-MMP inhibition. This is due to the inability of cells to activate integrinß1/FAK signaling, as restoration of integrinß1 activity is sufficient to maintain resistance to BRAFi in the context of MT1-MMP inhibition. Finally, the increase in MT1-MMP in BRAFi-resistant cells is TGFß-dependent, as inhibition of TGFb receptors I/II dampens MT1-MMP overexpression and restores sensitivity to BRAF inhibition.
    CONCLUSIONS: BRAF inhibition results in a selective pressure towards higher expression of MT1-MMP. MT1-MMP is pivotal to an ECM-based signaling pathway that confers resistance to BRAFi therapy.
  2. Cancer Res. 2020 Aug 19. pii: canres.0378.2020. [Epub ahead of print]
    Shiokawa D, Sakai H, Ohata H, Miyazaki T, Kanda Y, Sekine S, Narushima D, Hosokawa M, Kato M, Suzuki Y, Takeyama H, Kambara H, Nakagama H, Okamoto K.
      Cancer chemoresistance is often attributed to the presence of cancer stem cell (CSC)-like cells, but whether they are homogeneously chemoresistant remains unclear. We previously showed that in colon tumors, a subpopulation of LGR5+ CSC-like cells driven by TCF1 (TCF7), a Wnt-responsive transcription factor, were responsible for tumorigenicity. Here we demonstrate that the tumorigenic subpopulation of mouse LGR5+ cells exists in a slow-cycling state and identify a unique 22-gene signature that characterize these slow-cycling CSC. Seven of the signature genes are specifically expressed in slow-cycling LGR5+ cells from xenografted human colon tumors and are upregulated in colon cancer clinical specimens. Among these seven, four genes (APCDD1, NOTUM, PROX1, and SP5) are known to be direct Wnt target genes and PROX1 was expressed in the invasive fronts of colon tumors. PROX1 was activated by TCF1 to induce CDKN1C and maintain a slow-cycling state in colon cancer organoids. Strikingly, PROX1 was required for recurrent growth after chemotherapeutic treatment, suggesting that inhibition of slow-cycling CSC by targeting the TCF1-PROX1-CDKN1C pathway is an effective strategy to combat refractory colon cancer in combination with conventional chemotherapy.
  3. Proc Natl Acad Sci U S A. 2020 Aug 19. pii: 202008112. [Epub ahead of print]
    Itatani Y, Yamamoto T, Zhong C, Molinolo AA, Ruppel J, Hegde P, Taketo MM, Ferrara N.
      We tested cis-Apc Δ716 /Smad4 +/- and cis-Apc Δ716 /Smad4 +/- Kras G12D mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors in cis-Apc Δ716 /Smad4 +/- Kras G12D mice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) in cis-Apc Δ716 /Smad4 +/- and cis-Apc Δ716 /Smad4 +/- Kras G12D mice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents.
    Keywords:  angiogenesis; colorectal cancer; drug resistance; inflammation; myeloid cells
  4. Cancers (Basel). 2020 Aug 18. pii: E2324. [Epub ahead of print]12(8):
    Valcz G, Buzás EI, Sebestyén A, Krenács T, Szállási Z, Igaz P, Molnár B.
      Analogously to the natural selective forces in ecosystems, therapies impose selective pressure on cancer cells within tumors. Some tumor cells can adapt to this stress and are able to form resistant subpopulations, parallel with enrichment of cancer stem cell properties in the residual tumor masses. However, these therapy-resistant cells are unlikely to be sufficient for the fast tumor repopulation and regrowth by themselves. The dynamic and coordinated plasticity of residual tumor cells is essential both for the conversion of their regulatory network and for the stromal microenvironment to produce cancer supporting signals. In this nursing tissue "niche", cancer-associated fibroblasts are known to play crucial roles in developing therapy resistance and survival of residual stem-like cells. As paracrine messengers, extracellular vesicles carrying a wide range of signaling molecules with oncogenic potential, can support the escape of some tumor cells from their deadly fate. Here, we briefly overview how extracellular vesicle signaling between fibroblasts and cancer cells including cancer progenitor/stem cells may contribute to the progression, therapy resistance and recurrence of malignant tumors.
    Keywords:  cancer cell-fibroblast interaction; cancer stem cell; extracellular vesicles; therapy resistance
  5. Cancer Res. 2020 Aug 19. pii: canres.1255.2020. [Epub ahead of print]
    Rozeveld CN, Johnson KM, Zhang L, Razidlo GL.
      Oncogene-induced metabolic reprogramming is a hallmark of pancreatic cancer (PDAC), yet the metabolic drivers of metastasis are unclear. In PDAC, obesity and excess fatty acids accelerate tumor growth and increase metastasis. Here, we report that excess lipids, stored in organelles called lipid droplets (LD), are a key resource to fuel the energy-intensive process of metastasis. The oncogene KRAS controlled the storage and utilization of LD through regulation of hormone sensitive lipase (HSL), which was downregulated in human PDAC. Disruption of the KRAS-HSL axis reduced lipid storage, reprogrammed tumor cell metabolism, and inhibited invasive migration in vitro and metastasis in vivo. Finally, microscopy-based metabolic analysis revealed that migratory cells selectively utilize oxidative metabolism during the process of migration to metabolize stored lipids and fuel invasive migration. Taken together, these results reveal a mechanism that can be targeted to attenuate PDAC metastasis.
  6. Clin Cancer Res. 2020 Aug 21. pii: clincanres.3685.2019. [Epub ahead of print]
    Axelrod ML, Nixon MJ, Gonzalez-Ericsson PI, Bergman RE, Pilkinton MA, McDonnell WJ, Sanchez V, Opalenik S, Loi S, Zhou J, Mackay S, Rexer BN, Abramson VG, Jansen VM, Mallal SA, Donaldson J, Tolaney SM, Krop I, Garrido-Castro AC, Marotti JD, Shee K, Miller TW, Sanders M, Mayer IA, Salgado R, Balko JM.
      PURPOSE: The recent approval of anti-PD-L1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor-immune microenvironment (TIME).EXPERIMENTAL DESIGN: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). Additionally, we sought to characterize the systemic effects of NAC through single cell analysis (RNAseq and cytokine secretion) of PD-1HI CD8+ peripheral T cells and examination of a cytolytic gene signature in whole blood.
    RESULTS: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active anti-tumor immunity that may indicate ongoing disease burden.
    CONCLUSIONS: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.
  7. Theranostics. 2020 ;10(20): 9066-9082
    Zhang C, Wei S, Sun WP, Teng K, Dai MM, Wang FW, Chen JW, Ling H, Ma XD, Feng ZH, Duan JL, Cai MY, Xie D.
      Background and Aims: Aberrant transcriptional programs are highly regulated processes that play important roles in the development and progression of hepatocellular carcinoma (HCC). Emerging evidence suggests that super-enhancers (SEs) often drive critical oncogene expression. However, SE-associated genes in HCC pathogenesis are still poorly understood. Methods: We performed integrative ChIP-seq and Hi-C analyses of HCC cells and identified ajuba LIM protein (AJUBA) as a SE-associated gene. We evaluated AJUBA expression in HCC using immunohistochemistry, immunoblotting, and qRT-PCR. ChIP and luciferase reporter assays were performed to demonstrate that transcription factor 4 (TCF4) bound to AJUBA-associated SEs. We then assessed the role of AJUBA in HCC using both in vitro and in vivo assays. Epithelial-mesenchymal transition (EMT) was examined using immunofluorescence and immunoblotting assays. Furthermore, we used immunoprecipitation and BiFC assays to explore the underlying mechanisms. Results: We identified AJUBA as a SE-associated oncogene in HCC regulated by TCF4. High AJUBA expression was related to an aggressive phenotype and unfavorable outcome in HCC patients. AJUBA knockdown significantly reduced cell migration and invasion capacities both in vitro and in vivo. Furthermore, AJUBA overexpression in HCC recruited tumor necrosis factor associated factor 6 (TRAF6), enhancing the phosphorylation of Akt and increasing Akt activity toward GSK-3β, thus promoting EMT. Conclusions: Our results provide functional and mechanistic links between the SE-associated gene AJUBA and tumor EMT in aggressive HCC.
    Keywords:  AJUBA; EMT; TCF4; hepatocellular carcinoma; super-enhancer
  8. Cancer Res. 2020 Aug 15. 80(16): 3193-3194
    Wiley CD.
      Senescent cells release a mélange of factors that drive multiple forms of pathology, including cancer aggressiveness. In this issue of Cancer Research, Han and colleagues show that small extracellular vesicles (sEV), membrane-enclosed bubbles that carry signaling molecules, from senescent stromal cells can promote tumorigenesis and multidrug resistance in prostate or breast cancer cells. They find that loss of SIRT1 activity drives senescence-associated sEV release, and treatment with a SIRT1 agonist prevented this effect. This adds another mechanism by which senescent cells can promote tumorigenesis and offers another activity of senescent cells that might be targeted to limit the spread of cancer.See related article by Han et al., p. 3383.
  9. Mol Cancer. 2020 Aug 17. 19(1): 127
    Xu T, Wang M, Jiang L, Ma L, Wan L, Chen Q, Wei C, Wang Z.
      CircRNAs are a novel class of RNA molecules with a unique closed continuous loop structure. CircRNAs are abundant in eukaryotic cells, have unique stability and tissue specificity, and can play a biological regulatory role at various levels, such as transcriptional and posttranscriptional levels. Numerous studies have indicated that circRNAs serve a crucial purpose in cancer biology. CircRNAs regulate tumor behavioral phenotypes such as proliferation and migration through various molecular mechanisms, such as miRNA sponging, transcriptional regulation, and protein interaction. Recently, several reports have demonstrated that they are also deeply involved in resistance to anticancer drugs, from traditional chemotherapeutic drugs to targeted and immunotherapeutic drugs. This review is the first to summarize the latest research on circRNAs in anticancer drug resistance based on drug classification and to discuss their potential clinical applications.
    Keywords:  Cancer; Circular RNA; Drug; Resistance
  10. Proc Natl Acad Sci U S A. 2020 Aug 18. pii: 202010275. [Epub ahead of print]
    Khatib A, Solaimuthu B, Ben Yosef M, Abu Rmaileh A, Tanna M, Oren G, Schlesinger Frisch M, Axelrod JH, Lichtenstein M, Shaul YD.
      One of the emerging hallmarks of cancer illustrates the importance of metabolic reprogramming, necessary to synthesize the building blocks required to fulfill the high demands of rapidly proliferating cells. However, the proliferation-independent instructive role of metabolic enzymes in tumor plasticity is still unclear. Here, we provide evidence that glutathione peroxidase 8 (GPX8), a poorly characterized enzyme that resides in the endoplasmic reticulum, is an essential regulator of tumor aggressiveness. We found that GPX8 expression was induced by the epithelial-mesenchymal transition (EMT) program. Moreover, in breast cancer patients, GPX8 expression significantly correlated with known mesenchymal markers and poor prognosis. Strikingly, GPX8 knockout in mesenchymal-like cells (MDA-MB-231) resulted in an epithelial-like morphology, down-regulation of EMT characteristics, and loss of cancer stemness features. In addition, GPX8 knockout significantly delayed tumor initiation and decreased its growth rate in mice. We found that these GPX8 loss-dependent phenotypes were accompanied by the repression of crucial autocrine factors, in particular, interleukin-6 (IL-6). In these cells, IL-6 bound to the soluble receptor (sIL6R), stimulating the JAK/STAT3 signaling pathway by IL-6 trans-signaling mechanisms, so promoting cancer aggressiveness. We observed that in GPX8 knockout cells, this signaling mechanism was impaired as sIL6R failed to activate the JAK/STAT3 signaling pathway. Altogether, we present the GPX8/IL-6/STAT3 axis as a metabolic-inflammatory pathway that acts as a robust regulator of cancer cell aggressiveness.
    Keywords:  GPX8; JAK/STAT3 signaling; cancer metabolism; epithelial–mesenchymal transition
  11. Cancer Res. 2020 Aug 19. pii: canres.4028.2019. [Epub ahead of print]
    Urosevic J, Blasco MT, Llorente A, Bellmunt A, Berenguer-Llergo A, Guiu M, Cañellas A, Fernandez E, Burkov I, Clapés Cabrer M, Cartañá M, Figueras-Puig C, Batlle E, Nebreda AR, Gomis RR.
      Carcinoma development in colorectal cancer (CRC) is driven by genetic alterations in numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are associated with the shortest overall survival for patients after diagnosis of CRC metastatic disease, yet how RAS-ERK signaling regulates CRC metastasis remains unknown. In this study, we used an unbiased screening approach based on selection of highly liver metastatic CRC cells in vivo to determine genes associated with metastasis. From this, an ERK1/2-controlled metastatic gene set (EMGS) was defined. EMGS was associated with increased recurrence and reduced survival in patients with CRC tumors. Higher levels of EMGS expression were detected in the CRC subsets Consensus Molecular Subtype (CMS)1 and CMS4. ANGPT2 and CXCR4, two genes within the EMGS, were subjected to gain- and loss-of-function studies in several CRC cell lines and then tested in clinical samples. The RAS-ERK1/2 axis controlled expression of the cytokine ANGPT2 and the cytokine receptor CXCR4 in CRC cells, which facilitated development of liver but not lung metastases, suggesting that ANGPT2 and CXCR4 are important for metastatic outgrowth in the liver. CXCR4 controlled the expression of cytokines IL10 and CXCL1, providing evidence for a causal role of IL10 in supporting liver colonization. In summary, these studies demonstrate that amplification of ERK1/2 signaling in KRAS-mutated CRC cells affects the cytokine milieu of the tumors, possibly affecting tumor-stroma interactions and favoring liver metastasis formation.
  12. Science. 2020 Aug 21. 369(6506): 942-949
    Payne KK, Mine JA, Biswas S, Chaurio RA, Perales-Puchalt A, Anadon CM, Costich TL, Harro CM, Walrath J, Ming Q, Tcyganov E, Buras AL, Rigolizzo KE, Mandal G, Lajoie J, Ophir M, Tchou J, Marchion D, Luca VC, Bobrowicz P, McLaughlin B, Eskiocak U, Schmidt M, Cubillos-Ruiz JR, Rodriguez PC, Gabrilovich DI, Conejo-Garcia JR.
      Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate αβ and γδ T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive αβ T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of αβ T cell effector activity and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1+ cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αβ and γδ T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.
  13. Cancers (Basel). 2020 Aug 20. pii: E2350. [Epub ahead of print]12(9):
    Cohen R, Pudlarz T, Delattre JF, Colle R, André T.
      Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK).
    Keywords:  BRAF; HER2; NTRK; colorectal cancer; ctDNA; microsatellite instability
  14. Cancer Discov. 2020 Aug 14.
      Residual acute myeloid leukemia (AML) cells required bone marrow stromal cell-derived aspartate.
  15. Nature. 2020 Aug 19.
    Ubellacker JM, Tasdogan A, Ramesh V, Shen B, Mitchell EC, Martin-Sandoval MS, Gu Z, McCormick ML, Durham AB, Spitz DR, Zhao Z, Mathews TP, Morrison SJ.
      Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood1-4; however, the reason for this is unclear. Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with melanomas derived from patients, and immunocompetent mice with mouse melanomas, had more melanoma cells per microlitre in tumour-draining lymph than in tumour-draining blood. Cells that metastasized through blood, but not those that metastasized through lymph, became dependent on the ferroptosis inhibitor GPX4. Cells that were pretreated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid and less free iron in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumours. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than did melanoma cells from subcutaneous tumours. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.
  16. Cancer Res. 2020 Aug 14. pii: canres.1158.2020. [Epub ahead of print]
    El-Nikhely N, Karger A, Sarode P, Singh I, Weigert A, Wietelmann A, Stiewe T, Dammann R, Fink L, Grimminger F, Barreto G, Seeger W, Pullamsetti SS, Rapp UR, Savai R.
      Although NF-ƙB is known to play a pivotal role in lung cancer, contributing to tumor growth, microenvironmental changes, and metastasis, the epigenetic regulation of NF-ƙB in tumor context is largely unknown. Here we report that the IKK2/NF-ƙB signaling pathway modulates metastasis-associated protein 2 (MTA2), a component of the nucleosome remodeling and deacetylase complex (NuRD). In triple transgenic mice, downregulation of IKK2 (Sftpc-cRaf-IKK2DN) in cRaf-induced tumors in alveolar epithelial type-II cells restricted tumor formation, whereas activation of IKK2 (Sftpc-cRaf-IKK2CA) supported tumor growth; both effects were accompanied by altered expression of MTA2. Further studies employing genetic inhibition of MTA2 suggested that in primary tumor growth, independent of IKK2, MTA2/NuRD corepressor complex negatively regulates NF-ƙB signaling and tumor growth, while later dissociation of MTA2/NuRD complex from the promoter of NF-ƙB target genes and IKK2-dependent positive regulation of MTA2 leads to activation of NF-ƙB signaling, epithelial mesenchymal transition, and lung tumor metastasis. These findings reveal a previously unrecognized biphasic role of MTA2 in IKK2/NF-ƙB-driven primary-to-metastatic lung tumor progression. Addressing the interaction between MTA2 and NF-ƙB would provide potential targets for intervention of tumor growth and metastasis.
  17. Trends Cancer. 2020 Aug 14. pii: S2405-8033(20)30213-2. [Epub ahead of print]
    Reavis HD, Chen HI, Drapkin R.
      Over the past decade, several landmark reports have demonstrated that the nervous system plays an active role in cancer initiation and progression. These studies demonstrate that ablation of specific nerve types (parasympathetic, sympathetic, or sensory) abrogates tumor growth in a tissue-specific manner. Further, many tumor types are more densely innervated than their normal tissues of origin. These striking results raise fundamental questions regarding tumor innervation, how it is initiated, and how it molecularly contributes to disease. In this review, we aim to address what is currently known about the origin of tumor-infiltrating nerves, how they may be recruited to tumors, and how their presence may give rise to aggressive disease.
  18. Genes Dev. 2020 Aug 20.
    Grunblatt E, Wu N, Zhang H, Liu X, Norton JP, Ohol Y, Leger P, Hiatt JB, Eastwood EC, Thomas R, Ibrahim AH, Jia D, Basom R, Eaton KD, Martins R, Houghton AM, MacPherson D.
      Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. In treatment-naïve mice, MYCN overexpression promoted cell cycle progression, suppressed infiltration of cytotoxic T cells, and accelerated SCLC. MYCN overexpression also suppressed response to cisplatin-etoposide chemotherapy, with similar findings made upon MYCL overexpression. We extended these data to genetically perturb chemosensitive patient-derived xenograft (PDX) models of SCLC. In chemosensitive PDX models, overexpression of either MYCN or MYCL also conferred a switch to chemoresistance. To identify therapeutic strategies for MYCN-overexpressing SCLC, we performed a genome-scale CRISPR-Cas9 sgRNA screen. We identified the deubiquitinase USP7 as a MYCN-associated synthetic vulnerability. Pharmacological inhibition of USP7 resensitized chemoresistant MYCN-overexpressing PDX models to chemotherapy in vivo. Our findings show that MYCN overexpression drives SCLC chemoresistance and provide a therapeutic strategy to restore chemosensitivity.
    Keywords:  MYCL; MYCN; SCLC; USP7; chemoresistance
  19. Methods Mol Biol. 2021 ;2174 3-12
    Robles-Flores M.
      The inherent or developed resistance of many cancer cells to chemotherapy and irradiation is actually the main challenge to overcome in cancer treatment. It is well known that cancer cells are characterized by several hallmarks, and it seems that the ability to evolve ways to evade stressful conditions and killing therapies must be consider another typical characteristic displayed by all malignant cells. This overview aims to provide a concise description of the main mechanisms involved in the promotion of resistance to anticancer therapy and to describe the most frequent challenges faced in the war against cancer therapy resistance.
    Keywords:  Acquired resistance; Cancer resistance; Chemotherapy resistance; Intrinsic resistance; Therapy evasion
  20. Eur J Cancer. 2020 Aug 17. pii: S0959-8049(20)30393-2. [Epub ahead of print]138 1-10
    Cardone C, Blauensteiner B, Moreno-Viedma V, Martini G, Simeon V, Vitiello PP, Ciardiello D, Belli V, Matrone N, Troiani T, Morgillo F, Zito Marino F, Dentice M, Nappi A, Boccaccino A, Antoniotti C, Cremolini C, Pietrantonio F, Prager GW, Normanno N, Maiello E, Argiles G, Elez E, Signoriello G, Franco R, Falcone A, Tabernero J, Sibilia M, Ciardiello F, Martinelli E.
      BACKGROUND: RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC.METHODS: AXL was retrospectively assessed by immunohistochemistry in 307 patients. RAS wild-type (WT) patients (N = 136) received first-line anti-EGFR-based therapy; RAS mutant patients (N = 171) received anti-angiogenic-based regimens. Preclinical experiments were performed using human RAS WT CRC cell lines and xenograft models. AXL RNA levels were assessed in a cohort of patients with available samples at baseline and at progression to anti-EGFR treatment and in the GSE5851 dataset.
    RESULTS: AXL was expressed in 55/307 tumour tissues, correlating with worse survival in the overall population (AXL-positive, 23.7 months; AXL-negative, 30.8 months; HR, 1.455, P = 0.032) and in RAS WT patients (AXL-positive, 23.0 months; AXL-negative, 35.8 months; HR,1.780, P = 0.032). Progression-free survival (PFS) in the RAS WT cohort was shorter in the AXL-positive cohort (6.2 months versus 12.1 months; HR, 1.796, P = 0.013). Three-dimensional cultures obtained from a patient following anti-EGFR therapy resulted AXL-positive, showing resistance to anti-EGFR drugs and sensitivity to AXL inhibition. AXL transfection in CRC cell lines induced AXL overexpression and resistance to the EGFR blockade. At progression to cetuximab, 2/10 SW48-tumour xenograft mice showed AXL expression. Consistently, AXL RNA levels increased in 5/7 patients following anti-EGFR therapy. Moreover, in the GSE5851 dataset higher AXL RNA levels correlated with worse PFS with cetuximab in KRAS-exon2 WT chemorefractory patients.
    CONCLUSIONS: AXL is a marker of poor prognosis in mCRC with consistent clinical and preclinical evidences of involvement in primary and acquired resistance to anti-EGFR drugs in RAS WT patients.
    Keywords:  AXL; Colorectal cancer; EGFR resistance; RAS WT
  21. Nature. 2020 Aug 19.
    Wang H, Zhang XH.
    Keywords:  Ageing; Cancer; Metabolism
  22. Cell Stem Cell. 2020 Aug 14. pii: S1934-5909(20)30359-3. [Epub ahead of print]
    Jones CL, Stevens BM, Pollyea DA, Culp-Hill R, Reisz JA, Nemkov T, Gehrke S, Gamboni F, Krug A, Winters A, Pei S, Gustafson A, Ye H, Inguva A, Amaya M, Minhajuddin M, Abbott D, Becker MW, DeGregori J, Smith CA, D'Alessandro A, Jordan CT.
      We previously demonstrated that leukemia stem cells (LSCs) in de novo acute myeloid leukemia (AML) patients are selectively reliant on amino acid metabolism and that treatment with the combination of venetoclax and azacitidine (ven/aza) inhibits amino acid metabolism, leading to cell death. In contrast, ven/aza fails to eradicate LSCs in relapsed/refractory (R/R) patients, suggesting altered metabolic properties. Detailed metabolomic analysis revealed elevated nicotinamide metabolism in relapsed LSCs, which activates both amino acid metabolism and fatty acid oxidation to drive OXPHOS, thereby providing a means for LSCs to circumvent the cytotoxic effects of ven/aza therapy. Genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide metabolism, demonstrated selective eradication of R/R LSCs while sparing normal hematopoietic stem/progenitor cells. Altogether, these findings demonstrate that elevated nicotinamide metabolism is both the mechanistic basis for ven/aza resistance and a metabolic vulnerability of R/R LSCs.
    Keywords:  NAD+; NAMPT; acute myeloid leukemia; leukemia stem cells; metabolism; nicotinamide; oxidative phosphorylation; relapse; therapy resistance; venetoclax
  23. J Cell Biol. 2020 Sep 07. pii: e201912159. [Epub ahead of print]219(9):
    Farrugia AJ, Rodríguez J, Orgaz JL, Lucas M, Sanz-Moreno V, Calvo F.
      Fast amoeboid migration is critical for developmental processes and can be hijacked by cancer cells to enhance metastatic dissemination. This migratory behavior is tightly controlled by high levels of actomyosin contractility, but how it is coupled to other cytoskeletal components is poorly understood. Septins are increasingly recognized as novel cytoskeletal components, but details on their regulation and contribution to migration are lacking. Here, we show that the septin regulator Cdc42EP5 is consistently required for amoeboid melanoma cells to invade and migrate into collagen-rich matrices and locally invade and disseminate in vivo. Cdc42EP5 associates with actin structures, leading to increased actomyosin contractility and amoeboid migration. Cdc42EP5 affects these functions through SEPT9-dependent F-actin cross-linking, which enables the generation of F-actin bundles required for the sustained stabilization of highly contractile actomyosin structures. This study provides evidence that Cdc42EP5 is a regulator of cancer cell motility that coordinates actin and septin networks and describes a unique role for SEPT9 in melanoma invasion and metastasis.
  24. Elife. 2020 08 18. pii: e58123. [Epub ahead of print]9
    Zimmerli D, Borrelli C, Jauregi-Miguel A, Söderholm S, Brütsch S, Doumpas N, Reichmuth J, Murphy-Seiler F, Aguet M, Basler K, Moor AE, Cantù C.
      BCL9 and PYGO are β-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of β-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the β-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a β-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/β-catenin-dependent transcriptional complex.
    Keywords:  colorectal cancer; development; developmental biology; gene regulation; limb development; mouse; transcription; wnt signalling; zebrafish
  25. Cell. 2020 Aug 07. pii: S0092-8674(20)30882-5. [Epub ahead of print]
    Maynard A, McCoach CE, Rotow JK, Harris L, Haderk F, Kerr DL, Yu EA, Schenk EL, Tan W, Zee A, Tan M, Gui P, Lea T, Wu W, Urisman A, Jones K, Sit R, Kolli PK, Seeley E, Gesthalter Y, Le DD, Yamauchi KA, Naeger DM, Bandyopadhyay S, Shah K, Cech L, Thomas NJ, Gupta A, Gonzalez M, Do H, Tan L, Bacaltos B, Gomez-Sjoberg R, Gubens M, Jahan T, Kratz JR, Jablons D, Neff N, Doebele RC, Weissman J, Blakely CM, Darmanis S, Bivona TG.
      Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.
    Keywords:  ALK; EGFR; lung cancer; single-cell RNA sequencing; targeted therapy
  26. Cancers (Basel). 2020 Aug 12. pii: E2252. [Epub ahead of print]12(8):
    Varghese E, Samuel SM, Líšková A, Samec M, Kubatka P, Büsselberg D.
      Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC.
    Keywords:  anticancer drug; breast cancer; cancer; chemoresistance; glucose metabolism; resistance; sensitization; triple-negative breast cancer
  27. Nature. 2020 Aug 19.
    Grüner BM, Fendt SM.
    Keywords:  Cancer; Medical research; Metabolism
  28. Trends Cancer. 2020 Aug 13. pii: S2405-8033(20)30206-5. [Epub ahead of print]
  29. Cancer Res. 2020 Aug 14. pii: canres.1829.2020. [Epub ahead of print]
    Lauko A, Mu Z, Gutmann DH, Naik UP, Lathia JD.
      Tight junction (TJ) proteins are essential for mediating interactions between adjacent cells and coordinating cellular and organ responses. Initial investigations into TJ proteins and junctional adhesion molecules (JAM) in cancer suggested a tumor suppressive role where decreased expression led to increased metastasis. However, recent studies of the JAM family members JAM-A and JAM-C have expanded the roles of these proteins to include pro-tumorigenic functions, including inhibition of apoptosis and promotion of proliferation, cancer stem cell biology, and epithelial-to-mesenchymal transition. JAM function by interacting with other proteins through three distinct molecular mechanisms: direct cell-cell interaction on adjacent cells, stabilization of adjacent cell surface receptors on the same cell, and interactions between JAM and cell surface receptors expressed on adjacent cells. Collectively, these diverse interactions contribute to both the pro- and anti-tumorigenic functions of JAM. In this review, we discuss these context-dependent functions of JAM in a variety of cancers and highlight key areas that remain poorly understood, including their potentially diverse intracellular signaling networks, their roles in the tumor microenvironment, and the consequences of post-translational modifications on their function. These studies have implications in furthering our understanding of JAM in cancer and provide a paradigm for exploring additional roles of TJ proteins.
  30. Trends Cell Biol. 2020 Aug 13. pii: S0962-8924(20)30144-6. [Epub ahead of print]
    Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK.
      Cancer cell identity and plasticity are required in transition states, such as epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), in primary tumor initiation, progression, and metastasis. The functional roles of EMT, MET, and the partial state (referred to as pEMT) may vary based on the type of tumor, the state of dissemination, and the degree of metastatic colonization. Herein, we review EMT, MET, pEMT, and plasticity in the context of tumor metastasis.
    Keywords:  EMT; MET; cellular plasticity; colonization; metastasis; pEMT