bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒02‒07
23 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Oncogene. 2021 Feb;40(5): 997-1011
    Gu G, Tian L, Herzog SK, Rechoum Y, Gelsomino L, Gao M, Du L, Kim JA, Dustin D, Lo HC, Beyer AR, Edwards DG, Gonzalez T, Tsimelzon A, Huang HJ, Fernandez NM, Grimm SL, Hilsenbeck SG, Liu D, Xu J, Alaniz A, Li S, Mills GB, Janku F, Kittler R, Zhang XH, Coarfa C, Foulds CE, Symmans WF, Andò S, Fuqua SAW.
      Estrogen receptor alpha gene (ESR1) mutations occur frequently in ER-positive metastatic breast cancer, and confer clinical resistance to aromatase inhibitors. Expression of the ESR1 Y537S mutation induced an epithelial-mesenchymal transition (EMT) with cells exhibiting enhanced migration and invasion potential in vitro. When small subpopulations of Y537S ESR1 mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases. Y537S mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen (Tam) as well as to estradiol (E2) withdrawal. Y537S ESR1 mutant primary tumors metastasized efficiently in the absence of E2; however, Tam treatment significantly inhibited metastasis to distant sites. We identified a nine-gene expression signature, which predicted clinical outcomes of ER-positive breast cancer patients, as well as breast cancer metastasis to the lung. Androgen receptor (AR) protein levels were increased in mutant models, and the AR agonist dihydrotestosterone significantly inhibited estrogen-regulated gene expression, EMT, and distant metastasis in vivo, suggesting that AR may play a role in distant metastatic progression of ESR1 mutant tumors.
  2. Cancer Res. 2021 Feb 01. 81(3): 594-605
    Wyss CB, Duffey N, Peyvandi S, Barras D, Martinez Usatorre A, Coquoz O, Romero P, Delorenzi M, Lorusso G, Rüegg C.
      Early detection and adjuvant therapies have significantly improved survival of patients with breast cancer over the past three decades. In contrast, management of metastatic disease remains unresolved. Brain metastasis is a late complication frequently observed among patients with metastatic breast cancer, whose poor prognosis calls for novel and more effective therapies. Here, we report that active hypoxia inducible factor-1 (HIF1) signaling and loss of the miRNA let-7d concur to promote brain metastasis in a recently established model of spontaneous breast cancer metastasis from the primary site to the brain (4T1-BM2), and additionally in murine and human experimental models of breast cancer brain metastasis (D2A1-BM2 and MDA231-BrM2). Active HIF1 and let-7d loss upregulated expression of platelet-derived growth factor (PDGF) B/A in murine and human brain metastatic cells, respectively, while either individual silencing of HIF1α and PDGF-A/B or let-7d overexpression suppressed brain metastasis formation in the tested models. Let-7d silencing upregulated HIF1α expression and HIF1 activity, indicating a regulatory hierarchy of the system. The clinical relevance of the identified targets was supported by human gene expression data analyses. Treatment of mice with nilotinib, a kinase inhibitor impinging on PDGF receptor (PDGFR) signaling, prevented formation of spontaneous brain metastases in the 4T1-BM2 model and reduced growth of established brain metastases in mouse and human models. These results identify active HIF1 signaling and let-7d loss as coordinated events promoting breast cancer brain metastasis through increased expression of PDGF-A/B. Moreover, they identify PDGFR inhibition as a potentially actionable therapeutic strategy for patients with brain metastatis. SIGNIFICANCE: These findings show that loss of miRNA let-7d and active HIF1 signaling promotes breast cancer brain metastasis via PDGF and that pharmacologic inhibition of PDGFR suppresses brain metastasis, suggesting novel therapeutic opportunities. GRAPHICAL ABSTRACT: related article by Thies et al., p. 606.
  3. Nat Commun. 2021 02 03. 12(1): 769
    Tallón de Lara P, Castañón H, Vermeer M, Núñez N, Silina K, Sobottka B, Urdinez J, Cecconi V, Yagita H, Movahedian Attar F, Hiltbrunner S, Glarner I, Moch H, Tugues S, Becher B, van den Broek M.
      Some breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39+PD-1+CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNFα and IFNγ. Immunotherapy reduces the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevents metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not total CD8+ T cells correlates with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Thus, we suggest that a primary breast tumor could prime a systemic, CD39+PD-1+CD8+ T cell response that favors metastatic dormancy in the lungs.
  4. Cancer Res. 2021 Feb 01. pii: canres.CAN-20-3892-A.2020. [Epub ahead of print]
    Mueller AC, Piper M, Goodspeed A, Bhuvane S, Williams JS, Bhatia S, Phan AV, Van Court B, Zolman KL, Peña B, Oweida AJ, Zakem S, Meguid C, Knitz MW, Darragh L, Bickett TE, Gadwa J, Mestroni L, Taylor MRG, Jordan KR, Dempsey P, Lucia MS, McCarter MD, Del Chiaro M, Messersmith WA, Schulick RD, Goodman KA, Gough MJ, Greene CS, Costello JC, Galvao Neto A, Lagares D, Hansen KC, Van Bokhoven A, Karam SD.
      Stromal fibrosis activates pro-survival and pro-epithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell surface proteins, A disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after RT. RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with EphrinB2 FC-protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after radiation therapy and identifies a targetable pathway to enhance RT efficacy.
  5. Theranostics. 2021 ;11(7): 3196-3212
    Li K, Zhang Z, Mei Y, Yang Q, Qiao S, Ni C, Yao Y, Li X, Li M, Wei D, Fu W, Guo X, Huang X, Yang H.
      Resistance to chemotherapy is a long-standing problem in the management of cancer, and cancer stem cells are regarded as the main source of this resistance. This study aimed to investigate metallothionein (MT)-1G involvement in the regulation of cancer stemness and provide a strategy to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). Methods: MT1G was identified as a critical factor related with gemcitabine resistance in PDAC cells by mRNA microarray. Its effects on PDAC stemness were evaluated through sphere formation and tumorigenicity. LC-MS/MS analysis of conditional medium revealed that activin A, a NF-κB target, was a major protein secreted from gemcitabine resistant PDAC cells. Both loss-of-function and gain-of-function approaches were used to validate that MT1G inhibited NF-κB-activin A pathway. Orthotopic pancreatic tumor model was employed to explore the effects on gemcitabine resistance with recombinant follistatin to block activin A. Results: Downregulation of MT1G due to hypermethylation of its promoter is related with pancreatic cancer stemness. Secretome analysis revealed that activin A, a NF-κB target, was highly secreted by drug resistant cells. It promotes pancreatic cancer stemness in Smad4-dependent or independent manners. Mechanistically, MT1G negatively regulates NF-κB signaling and promotes the degradation of NF-κB p65 subunit by enhancing the expression of E3 ligase TRAF7. Blockade of activin A signaling with follistatin could overcome gemcitabine resistance. Conclusions: MT1G suppresses PDAC stemness by limiting activin A secretion via NF-κB inhibition. The blockade of the activin A signaling with follistatin may provide a promising therapeutic strategy for overcoming gemcitabine resistance in PDAC.
    Keywords:  MT1G; PDAC stemness; activin A; follistatin; gemcitabine resistance
  6. Clin Cancer Res. 2021 Feb 05. pii: clincanres.4699.2020. [Epub ahead of print]
    Manca P, Corallo S, Busico A, Lonardi S, Corti F, Antoniotti C, Procaccio L, Clavarezza M, Smiroldo V, Tomasello G, Murialdo R, Sartore-Bianchi A, Racca P, Pagani F, Randon G, Martinetti A, Sottotetti E, Palermo F, Perrone F, Tamborini E, Prisciandaro M, Raimondi A, Di Bartolomeo M, Morano F, Pietrantonio F.
      BACKGROUND: The routine use of liquid biopsy is not recommended for the choice of initial treatment of patients with metastatic colorectal cancer (mCRC).EXPERIMENTAL DESIGN: We included patients with left-sided, RAS/BRAF wild-type, HER2-negative and microsatellite stable mCRC, treated with upfront FOLFOX-panitumumab in the Valentino study. We performed amplicon-based genomic profiling of 14 genes in baseline plasma samples and compared these data with tumor tissue ultra-deep sequencing results. Specific gene mutations in ctDNA and their clonality were associated with PFS, OS and radiological dynamics.
    RESULTS: Ten and 15 out of 120 patients had a mutation of RAS and PIK3CA in ctDNA, with a positive concordance with tissue deep-sequencing of only 31.3% and 47.1%, respectively. Presence of RAS or PIK3CA mutations in baseline ctDNA was associated with worse median PFS (8.0 vs. 12.8 months; HR=2.49, 95%CI: 1.28-4.81, p=0.007; 8.5 vs 12.9 months; HR=2.86, 95%CI: 1.63-5.04, p<0.001) and median OS (17.1 vs. 36.5 months; HR=2.26, 95%CI: 1.03-4.96, p=0.042; 21.1 vs 38.9 months; HR=2.18, 95%CI: 1.16-4.07, p=0.015). RAS mutations in ctDNA were associated with worse RECIST response, early tumor shrinkage and depth of response, while PIK3CA mutations were not. Patients with higher levels of RAS/PIK3CA variant allele fraction (VAF) in ctDNA had the worst outcomes (VAF {greater than or equal to}5% vs all-wild-type: median PFS: 7.7 vs 13.1 months, HR: 4.02, 95%CI: 2.03-7.95, p<0.001; median OS: 18.8 vs 38.9 months, HR: 4.07, 95%CI: 2.04-8.12, p<0.001).
    CONCLUSION: Baseline ctDNA profiling may add value to tumor tissue testing to refine the molecular hyperselection of mCRC patients for upfront anti-EGFR-based strategies.
  7. Elife. 2021 Feb 02. pii: e64370. [Epub ahead of print]10
    Fazio M, van Rooijen E, Dang M, van de Hoek G, Ablain J, Mito JK, Yang S, Thomas A, Michael J, Fabo T, Modhurima R, Pessina P, Kaufman CK, Zhou Y, White RM, Zon LI.
      Recent genomic and scRNA-seq analyses of melanoma demonstrated a lack of recurrent genetic drivers of metastasis, while identifying common transcriptional states correlating with invasion or drug resistance. To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafish mitfa:BRAFV600E;tp53-/- model, in which malignant progression is characterized by minimal genetic evolution. We undertook an overexpression-screen of 80 epigenetic/transcriptional regulators and found neural crest-mesenchyme developmental regulator SATB2 to accelerate aggressive melanoma development. Its overexpression induces invadopodia formation and invasion in zebrafish tumors and human melanoma cell lines. SATB2 binds and activates neural crest-regulators, including pdgfab and snai2. The transcriptional program induced by SATB2 overlaps with known MITFlowAXLhigh and AQP1+NGFR1high drug resistant states and functionally drives enhanced tumor propagation and resistance to Vemurafenib in vivo. Here we show that melanoma transcriptional rewiring by SATB2 to a neural crest mesenchyme-like program can drive invasion and drug resistance in endogenous tumors.
    Keywords:  cancer biology; zebrafish
  8. Mol Ther. 2021 Feb 02. pii: S1525-0016(21)00065-4. [Epub ahead of print]
    Zhu J, Luo Y, Zhao Y, Kong Y, Zheng H, Li Y, Gao B, Ai L, Huang H, Huang J, Li Z, Chen C.
      Lymphatic metastasis constitutes a leading cause of recurrence and mortality in bladder cancer. Accumulating evidence indicates that lymphangiogenesis is indispensable to trigger lymphatic metastasis. However, the specific mechanism is poorly understood. In the present study, we revealed a pathway involved in lymphatic metastasis of bladder cancer, in which a circular RNA (circRNA) facilitated lymphangiogenesis in a vascular endothelial growth factor C (VEGF-C) independent manner. Novel circRNA circEHBP1 was markedly upregulated in bladder cancer and correlated positively with lymphatic metastasis and poor prognosis of patients with bladder cancer. CircEHBP1 upregulated transforming growth factor beta receptor 1 (TGFBR1) expression through physically binding to miR-130a-3p and antagonizing the suppression effect of miR-130a-3p on the 3' UTR region of TGFBR1. Subsequently, circEHBP1-mediated TGFβR1 overexpression activated the TGF-β/SMAD3 signaling pathway, thereby promoting the secretion of VEGF-D and driving lymphangiogenesis and lymphatic metastasis in bladder cancer. Importantly, administration of VEGF-D neutralizing antibodies remarkably blocked circEHBP1-induced lymphangiogenesis and lymphatic metastasis in vivo. Our findings highlighted that the circEHBP1/miR-130a-3p/TGFβR1/VEGF-D axis contributes to lymphangiogenesis and lymphatic metastasis of bladder cancer independent of VEGF-C, which might lead to the development of circEHBP1 as a potential biomarker and promising therapeutic target for lymphatic metastasis in bladder cancer.
    Keywords:  CircRNA; TGF-β pathway; VEGF-D; bladder cancer; lymphangiogenesis
  9. Oncogene. 2021 Feb 02.
    Varone E, Decio A, Chernorudskiy A, Minoli L, Brunelli L, Ioli F, Piotti A, Pastorelli R, Fratelli M, Gobbi M, Giavazzi R, Zito E.
      Solid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at restoring ER homeostasis. We studied ERO1 alpha (henceforth ERO1), a protein disulfide oxidase with the tumor-relevant characteristic of being positively regulated by both ER stress and hypoxia. Analysis of the redox secretome indicated that pro-angiogenic HIF-1 targets, were blunted in ERO1-devoid breast cancer cells under hypoxic conditions. ERO1 deficiency reduced tumor cell migration and lung metastases by impinging on tumor angiogenesis, negatively regulating the upstream ATF4/CHOP branch of the UPR and selectively impeding oxidative folding of angiogenic factors, among which VEGF-A. Thus, ERO1 deficiency acted synergistically with the otherwise feeble curative effects of anti-angiogenic therapy in aggressive breast cancer murine models and it might be exploited to treat cancers with pathological HIF-1-dependent angiogenesis. Furthermore, ERO1 levels are higher in the more aggressive basal breast tumors and correlate inversely with the disease- and metastasis-free interval of breast cancer patients. Thus, taking advantage of our in vitro data on ERO1-regulated gene products we identified a gene set associated with ERO1 expression in basal tumors and related to UPR, hypoxia, and angiogenesis, whose levels might be investigated in patients as a hallmark of tumor aggressiveness and orient those with lower levels toward an effective anti-angiogenic therapy.
  10. Nat Commun. 2021 02 01. 12(1): 723
    McGuire JJ, Frieling JS, Lo CH, Li T, Muhammad A, Lawrence HR, Lawrence NJ, Cook LM, Lynch CC.
      Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.
  11. Cancer Res. 2021 Feb 02. pii: canres.1034.2020. [Epub ahead of print]
    Singh S, Sutcliffe MD, Repich K, Atkins KA, Harvey JA, Janes KA.
      The heterogeneous composition of solid tumors is known to impact disease progression and response to therapy. Malignant cells coexist in different regulatory states that can be accessed transcriptomically by single-cell RNA sequencing, but these methods have many caveats related to sensitivity, noise, and sample handling. We revised a statistical fluctuation analysis called stochastic profiling to combine with 10-cell RNA sequencing, which was designed for laser-capture microdissection (LCM) and extended here for immuno-LCM. When applied to a cohort of late-onset, early-stage luminal breast cancers, the integrated approach identified thousands of candidate regulatory heterogeneities. Intersecting the candidates from different tumors yielded a relatively stable set of 710 recurrent heterogeneously expressed genes (RHEG) that were significantly variable in >50% of patients. RHEGs were not strongly confounded by dissociation artifacts, cell cycle oscillations, or driving mutations for breast cancer. Rather, RHEGs were enriched for epithelial-to-mesenchymal transition genes and, unexpectedly, the latest pan-cancer assembly of driver genes across cancer types other than breast. These findings indicate that heterogeneous transcriptional regulation conceivably provides a faster, reversible mechanism for malignant cells to evaluate the effects of potential oncogenes or tumor suppressors on cancer hallmarks.
  12. Nat Cancer. 2020 Apr;1 423-436
    Stewart CA, Gay CM, Xi Y, Sivajothi S, Sivakamasundari V, Fujimoto J, Bolisetty M, Hartsfield PM, Balasubramaniyan V, Chalishazar MD, Moran C, Kalhor N, Stewart J, Tran H, Swisher SG, Roth JA, Zhang J, de Groot J, Glisson B, Oliver TG, Heymach JV, Wistuba I, Robson P, Wang J, Byers LA.
      The natural history of small cell lung cancer (SCLC) includes rapid evolution from chemosensitivity to chemoresistance, although mechanisms underlying this evolution remain obscure due to scarcity of post-relapse tissue samples. We generated circulating tumor cell (CTC)-derived xenografts (CDXs) from SCLC patients to study intratumoral heterogeneity (ITH) via single-cell RNAseq of chemo-sensitive and -resistant CDXs and patient CTCs. We found globally increased ITH including heterogeneous expression of therapeutic targets and potential resistance pathways, such as EMT, between cellular subpopulations following treatment-resistance. Similarly, serial profiling of patient CTCs directly from blood confirmed increased ITH post-relapse. These data suggest that treatment-resistance in SCLC is characterized by coexisting subpopulations of cells with heterogeneous gene expression leading to multiple, concurrent resistance mechanisms. These findings emphasize the need for clinical efforts to focus on rational combination therapies for treatment-naïve SCLC tumors to maximize initial responses and counteract the emergence of ITH and diverse resistance mechanisms.
    Keywords:  CDX; CTC; SCLC; intratumoral heterogeneity; single-cell RNAseq
  13. Clin Cancer Res. 2021 Feb 05. pii: clincanres.4179.2019. [Epub ahead of print]
    Mudianto T, Campbell KM, Webb J, Zolkind P, Skidmore ZL, Riley R, Barnell EK, Ozgenc I, Giri T, Dunn GP, Adkins DR, Griffith M, Egloff AM, Griffith OL, Uppaluri R.
      PURPOSE: In a head and neck squamous cell carcinoma (HNSCC) "window of opportunity" clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples.EXPERIMENTAL DESIGN: HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDX) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole exome and RNA sequencing.
    RESULTS: HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity.
    CONCLUSIONS: These studies identify a Yap1 dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response.
  14. Oncogene. 2021 Feb 01.
    Wood GE, Hockings H, Hilton DM, Kermorgant S.
      Chemotherapy remains the mainstay of treatment in the majority of solid and haematological malignancies. Resistance to cytotoxic chemotherapy is a major clinical problem and substantial research is ongoing into potential methods of overcoming this resistance. One major target, the receptor tyrosine kinase MET, has generated increasing interest with multiple clinical trials in progress. Overexpression of MET is frequently observed in a range of different cancers and is associated with poor prognosis. Studies have shown that MET promotes resistance to targeted therapies, including those targeting EGFR, BRAF and MEK. More recently, several reports suggest that MET also contributes to cytotoxic chemotherapy resistance. Here we review the preclinical evidence of MET's role in chemotherapy resistance, the mechanisms by which this resistance is mediated and the translational relevance of MET inhibitor therapy for patients with chemotherapy resistant disease.
  15. Clin Cancer Res. 2021 Feb 04. pii: clincanres.3260.2020. [Epub ahead of print]
    Liang Y, Jeganathan S, Marastoni S, Sharp A, Figueiredo I, Marcellus R, Mawson A, Shalev Z, Pesic A, Sweet J, Guo H, Uehling D, Gurel B, Neeb AJ, He HH, Montgomery B, Koritzinsky M, Oakes SR, de Bono JS, Gleave ME, Zoubeidi A, Wouters BG, Joshua AM.
      PURPOSE: Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops, and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ-resistance.EXPERIMENTAL DESIGN: We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high- throughput pharmacological screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared to parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knock-down and over- expression assays to study the dependencies in ENZ-resistant prostate cancer.
    RESULTS: ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor), were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of enzalutamide/abiraterone resistance in patients, only the protein levels of IKKB were increased.
    CONCLUSIONS: Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate resistant prostate cancer.
  16. Nature. 2021 Feb 03.
    Alonso-Curbelo D, Ho YJ, Burdziak C, Maag JLV, Morris JP, Chandwani R, Chen HA, Tsanov KM, Barriga FM, Luan W, Tasdemir N, Livshits G, Azizi E, Chun J, Wilkinson JE, Mazutis L, Leach SD, Koche R, Pe'er D, Lowe SW.
      Tissue damage increases the risk of cancer through poorly understood mechanisms1. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma2,3. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an 'acinar-to-neoplasia' chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.
  17. Trends Cancer. 2021 Feb 01. pii: S2405-8033(20)30334-4. [Epub ahead of print]
    Huang S.
      Post-treatment progression of tumors is commonly explained by somatic Darwinian evolution (i.e., selection of cells carrying genetic mutations that create more aggressive cell traits). But cancer genome and transcriptome analyses now paint a picture far more complex, prompting us to see beyond the Darwinian scheme: non-genetic cell phenotype plasticity explained by alternative stable gene expression states ('attractors'), may also produce aggressive phenotypes that can be selected for, without mutations. Worse, treatment may even induce cell state transitions into more malignant attractors. We review recent evidence for non-genetic mechanisms of progression, explain the theoretical foundation of attractor transitions behind treatment-induced increase of aggressiveness, and provide a framework for unifying genetic and non-genetic dynamics in tumor progression.
    Keywords:  attractor states; non-genetic plasticity; treatment resistance; treatment-induced progression
  18. Cancer Discov. 2021 Feb 05.
      Knockout of any of several noncanonical open reading frames (ORF) impaired cancer cell survival.
  19. Commun Biol. 2021 Feb 05. 4(1): 166
    Dufies M, Verbiest A, Cooley LS, Ndiaye PD, He X, Nottet N, Souleyreau W, Hagege A, Torrino S, Parola J, Giuliano S, Borchiellini D, Schiappa R, Mograbi B, Zucman-Rossi J, Bensalah K, Ravaud A, Auberger P, Bikfalvi A, Chamorey E, Rioux-Leclercq N, Mazure NM, Beuselinck B, Cao Y, Bernhard JC, Ambrosetti D, Pagès G.
      Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients.
  20. Oncogene. 2021 Feb 03.
    Pan JK, Lin CH, Kuo YL, Ger LP, Cheng HC, Yao YC, Hsiao M, Lu PJ.
      Brian metastasis, which is diagnosed in 30% of triple-negative breast cancer (TNBC) patients with metastasis, causes poor survival outcomes. Growing evidence has characterized miRNAs involving in breast cancer brain metastasis; however, currently, there is a lack of prognostic plasma-based indicator for brain metastasis. In this study, high level of miR-211 can act as brain metastatic prognostic marker in vivo. High miR-211 drives early and specific brain colonization through enhancing trans-blood-brain barrier (BBB) migration, BBB adherence, and stemness properties of tumor cells and causes poor survival in vivo. SOX11 and NGN2 are the downstream targets of miR-211 and negatively regulate miR-211-mediated TNBC brain metastasis in vitro and in vivo. Most importantly, high miR-211 is correlated with poor survival and brain metastasis in TNBC patients. Our findings suggest that miR-211 may be used as an indicator for TNBC brain metastasis.
  21. Cancer Res. 2021 Feb 01. pii: canres.1541.2020. [Epub ahead of print]
    Montrose DC, Saha S, Foronda M, McNally EM, Chen J, Zhou XK, Ha T, Krumsiek J, Buyukozkan M, Verma A, Elemento O, Yantiss RK, Chen Q, Gross SS, Galluzzi L, Dow LE, Dannenberg AJ.
      Serine is a non-essential amino acid generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1), and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. Additionally, cancer cells can harness exogenous serine to enhance their metabolism and proliferation. Here we tested the relative contributions of exogenous and endogenous sources of serine on the biology of colorectal cancer (CRC). In murine tumors, Apc status was identified as a determinant of the expression of genes controlling serine synthesis. In patient samples, PSAT1 was overexpressed in both colorectal adenomas and adenocarcinomas. Combining genetic deletion of PSAT1 with exogenous serine deprivation maximally suppressed the proliferation of CRC cells and induced profound metabolic defects including diminished nucleotide production. Inhibition of serine synthesis enhanced the transcriptional changes following exogenous serine removal as well as alterations associated with DNA damage. Both loss of PSAT1 and removal of serine from the diet were necessary to suppress CRC xenograft growth and enhance the anti-tumor activity of 5-fluorouracil (5-FU). Restricting endogenous and exogenous serine in vitro augmented 5-FU induced cell death, DNA damage, and metabolic perturbations, likely accounting for the observed anti-tumor effect. Collectively, our results suggest that both endogenous and exogenous sources of serine contribute to CRC growth and resistance to 5-FU.
  22. Nat Rev Cancer. 2021 Feb 05.
    Lambert AW, Weinberg RA.
      Epithelial stem cells serve critical physiological functions in the generation, maintenance and repair of diverse tissues through their ability to self-renew and spawn more specialized, differentiated cell types. In an analogous fashion, cancer stem cells have been proposed to fuel the growth, progression and recurrence of many carcinomas. Activation of an epithelial-mesenchymal transition (EMT), a latent cell-biological programme involved in development and wound healing, has been linked to the formation of both normal and neoplastic stem cells, but the mechanistic basis underlying this connection remains unclear. In this Perspective, we outline the instances where aspects of an EMT have been implicated in normal and neoplastic epithelial stem cells and consider the involvement of this programme during tissue regeneration and repair. We also discuss emerging concepts and evidence related to the heterogeneous and plastic cell states generated by EMT programmes and how these bear on our understanding of cancer stem cell biology and cancer metastasis. A more comprehensive accounting of the still-elusive links between EMT programmes and the stem cell state will surely advance our understanding of both normal stem cell biology and cancer pathogenesis.