bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒11‒08
twenty-five papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. EMBO Mol Med. 2020 Nov 05. e11889
    Moserle L, Pons R, Martínez-Lozano M, Jiménez-Valerio GA, Vidal A, Suárez C, Trilla E, Jiménez J, de Torres I, Carles J, Senserrich J, Aguilar S, Palomero L, Amadori A, Casanovas O.
      An open debate in antiangiogenic therapies is about their consequence on tumor invasiveness and metastasis, which is undoubtedly relevant for patients currently treated with antiangiogenics, such as renal cell carcinoma patients. To address, this we developed an extensive series of 27 patient biopsy-derived orthotopic xenograft models (Ren-PDOX) that represent inter-patient heterogeneity. In specific tumors, antiangiogenics produced increased invasiveness and metastatic dissemination, while in others aggressiveness remained unchanged. Mechanistically, species-discriminative RNA sequencing identified a tumor cell-specific differential expression profile associated with tumor progression and aggressivity in TCGA RCC patients. Gene filtering using an invasion-annotated patient series pinpointed two candidate genes, of which ALDH1A3 differentiated the pro-invasive subtype of Ren-PDOXs. Validation in an independent series of 15 antiangiogenic-treated patients confirmed that pre-treatment ALDH1A3 can significantly discriminate patients with pro-aggressive response upon treatment. Overall, results confirm that effects of antiangiogenic drugs on tumor invasion and metastasis are heterogeneous and may profoundly affect the natural progression of tumors and promote malignancy. Furthermore, we identify a specific molecular biomarker that could be used to select patients that better benefit from treatment.
    Keywords:  antiangiogenics; biomarker; cancer resistance; metastasis induction; orthotopic models of kidney cancer
    DOI:  https://doi.org/10.15252/emmm.201911889
  2. Genome Biol. 2020 Nov 04. 21(1): 271
    Lee WC, Reuben A, Hu X, McGranahan N, Chen R, Jalali A, Negrao MV, Hubert SM, Tang C, Wu CC, Lucas AS, Roh W, Suda K, Kim J, Tan AC, Peng DH, Lu W, Tang X, Chow CW, Fujimoto J, Behrens C, Kalhor N, Fukumura K, Coyle M, Thornton R, Gumbs C, Li J, Wu CJ, Little L, Roarty E, Song X, Lee JJ, Sulman EP, Rao G, Swisher S, Diao L, Wang J, Heymach JV, Huse JT, Scheet P, Wistuba II, Gibbons DL, Futreal PA, Zhang J, Gomez D, Zhang J.
      BACKGROUND: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary.RESULTS: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases.
    CONCLUSIONS: Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.
    Keywords:  DNA methylation; Gene expression; Genomics; Immune profiling; Lung cancer; Metastasis; Multiomics
    DOI:  https://doi.org/10.1186/s13059-020-02175-0
  3. Nat Commun. 2020 11 02. 11(1): 5513
    Shi Q, Li Y, Li S, Jin L, Lai H, Wu Y, Cai Z, Zhu M, Li Q, Li Y, Wang J, Liu Y, Wu Z, Song E, Liu Q.
      Cyclin D1 is one of the most important oncoproteins that drives cancer cell proliferation and associates with tamoxifen resistance in breast cancer. Here, we identify a lncRNA, DILA1, which interacts with Cyclin D1 and is overexpressed in tamoxifen-resistant breast cancer cells. Mechanistically, DILA1 inhibits the phosphorylation of Cyclin D1 at Thr286 by directly interacting with Thr286 and blocking its subsequent degradation, leading to overexpressed Cyclin D1 protein in breast cancer. Knocking down DILA1 decreases Cyclin D1 protein expression, inhibits cancer cell growth and restores tamoxifen sensitivity both in vitro and in vivo. High expression of DILA1 is associated with overexpressed Cyclin D1 protein and poor prognosis in breast cancer patients who received tamoxifen treatment. This study shows the previously unappreciated importance of post-translational dysregulation of Cyclin D1 contributing to tamoxifen resistance in breast cancer. Moreover, it reveals the novel mechanism of DILA1 in regulating Cyclin D1 protein stability and suggests DILA1 is a specific therapeutic target to downregulate Cyclin D1 protein and reverse tamoxifen resistance in treating breast cancer.
    DOI:  https://doi.org/10.1038/s41467-020-19349-w
  4. Cancer Discov. 2020 Nov 06. pii: CD-20-0455. [Epub ahead of print]
    Zhang S, Iyer S, Ran H, Dolgalev I, Gu S, Wei W, Foster CJR, Loomis CA, Olvera N, Dao F, Levine DA, Weinberg RA, Neel BG.
      The paucity of genetically informed, immune-competent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube epithelial organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high grade serous tubo-ovarian carcinoma (HGSC) models exhibiting mutational combinations seen in HGSC patients. Detailed analysis of homologous recombination (HR)-proficient (Tp53-/-;Ccne1OE;Akt2OE ;KrasOE), HR-deficient (Tp53-/-;Brca1-/-;MycOE), and unclassified (Tp53-/-;Pten-/-;Nf1-/-) organoids revealed differences in in vitro properties (proliferation, differentiation, "secretome"), copy number aberrations, and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSC chemotherapeutics, evoked distinct immune microenvironments that could be modulated by neutralizing organoid-produced chemokines/cytokines. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T-cell dependent responses in Tp53-/-;Ccne1OE;Akt2OE;Kras HGSC; by contrast, Tp53-/-;Pten-/-;Nf1-/- tumors failed to respond. Mouse and human HGSC models showed genotype-dependent similarities in chemosensitivity, secretome, and immune microenvironment. Genotype-informed, syngeneic organoid models could provide a platform for the rapid evaluation of tumor biology and therapeutics.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0455
  5. Mol Cancer. 2020 Nov 05. 19(1): 156
    Peng L, Sang H, Wei S, Li Y, Jin D, Zhu X, Li X, Dang Y, Zhang G.
      BACKGROUND: Circular RNAs (circRNAs) are a class of noncoding RNAs (ncRNAs) and can modulate gene expression by binding to miRNAs; further, circRNAs have been shown to participate in several pathological processes. However, the expression and biological function of circCUL2 in gastric cancer (GC) remains largely unknown.METHODS: circRNA microarrays and quantitative real-time PCR (qRT-PCR) were used to identify differentially expressed circRNAs in GC tissues and cell lines. circCUL2 knockdown and overexpression were performed to indicate the functional role of circCUL2 in vitro and in vivo. The expression and regulation of circCUL2, miR-142-3p and ROCK2 were evaluated using fluorescence in situ hybridization (FISH), dual-luciferase assays, RNA pull-down assays, RNA immunoprecipitation (RIP) and rescue experiments. Furthermore, the regulation of cisplatin sensitivity and autophagy by circCUL2/miR-142-3p/ROCK2 was demonstrated by cellular apoptosis assays, western blot, immunofluorescence and transmission electron microscopy analyses.
    RESULTS: The level of circCUL2, which is stable and cytoplasmically localized, was significantly reduced in GC tissues and cells. Overexpressed circCUL2 inhibited malignant transformation in vitro and tumorigenicity in vivo. In the AGS and SGC-7901 cell lines, circCUL2 sponged miR-142-3p to regulate ROCK2, thus modulating tumor progression. Furthermore, in the AGS/DDP and SGC-7901/DDP cell lines, circCUL2 regulated cisplatin sensitivity through miR-142-3p/ROCK2-mediated autophagy activation.
    CONCLUSION: circCUL2 may function as a tumor suppressor and regulator of cisplatin sensitivity through miR-142-3p/ROCK2-mediated autophagy activation, which could be a key mechanism and therapeutic target for GC.
    Keywords:  Autophagy; Cisplatin resistance; Gastric cancer; ROCK2; circCUL2; miR-142-3p
    DOI:  https://doi.org/10.1186/s12943-020-01270-x
  6. Cancer Metastasis Rev. 2020 Nov 06.
    Cheng X, Cheng K.
      Metastasis is a multistep process that accounts for the majority of cancer-related death. By the end of metastasize dissemination, circulating tumor cells (CTC) need to extravasate the blood vessels at metastatic sites to form new colonization. Although cancer cell extravasation is a crucial step in cancer metastasis, it has not been successfully targeted by current anti-metastasis strategies due to the lack of a thorough understanding of the molecular mechanisms that regulate this process. This review focuses on recent progress in cancer extravasation visualization techniques, including the development of both in vitro and in vivo cancer extravasation models, that shed light on the underlying mechanisms. Specifically, multiple cancer extravasation stages, such as the adhesion to the endothelium and transendothelial migration, are successfully probed using these technologies. Moreover, the roles of different cell adhesive molecules, chemokines, and growth factors, as well as the mechanical factors in these stages are well illustrated. Deeper understandings of cancer extravasation mechanisms offer us new opportunities to escalate the discovery of anti-extravasation drugs and therapies and improve the prognosis of cancer patients.
    Keywords:  Cancer cell extravasation; Cancer metastasis; Cancer models; Cancer therapies
    DOI:  https://doi.org/10.1007/s10555-020-09942-2
  7. Cancer Res. 2020 Nov 06. pii: canres.3922.2019. [Epub ahead of print]
    Tomihara H, Carbone F, Perelli L, Huang JK, Soeung M, Rose JL, Robinson FS, Lissanu Deribe Y, Feng N, Takeda M, Inoue A, Deem AK, Maitra A, Msaouel P, Tannir NM, Draetta GF, Bristow CA, Carugo A, Genovese G.
      Cellular de-differentiation is a key mechanism driving cancer progression. Acquisition of mesenchymal features has been associated with drug resistance, poor prognosis, and disease relapse in many tumor types. Therefore, successful targeting of tumors harboring these characteristics is a priority in oncology practice. The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex has also emerged as a critical player in tumor progression, leading to the identification of several SWI/SNF complex genes as potential disease biomarkers and targets of anti-cancer therapies. AT-rich interaction domain-containing protein 1A (ARID1A) is a component of SWI/SNF, and mutations in ARID1A represent one of the most frequent molecular alterations in human cancers. ARID1A mutations occur in ~10% of pancreatic ductal adenocarcinomas (PDAC), but whether these mutations confer a therapeutic opportunity remains unclear. Here we demonstrate that loss of ARID1A promotes an epithelial-mesenchymal transition (EMT) phenotype and sensitizes PDAC cells to a clinical inhibitor of HSP90, NVP-AUY922, both in vitro and in vivo. While loss of ARID1A alone did not significantly affect proliferative potential or rate of apoptosis, ARID1A-deficient cells were sensitized to HSP90 inhibition, potentially by promoting the degradation of intermediate filaments driving EMT, resulting in cell death. Our results describe a mechanistic link between ARID1A defects and a quasi-mesenchymal phenotype, suggesting that deleterious mutations in ARID1A associated with protein loss exhibits potential as a biomarker for PDAC patients who may benefit by HSP90-targeting drugs treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3922
  8. Cancers (Basel). 2020 Nov 02. pii: E3227. [Epub ahead of print]12(11):
    Muresan XM, Bouchal J, Culig Z, Souček K.
      Toll-like receptor 3 (TLR3) is a member of the TLR family, which has been extensively studied for its antiviral function. It is highly expressed in the endosomes of antigen-presenting immune cells and epithelial cells. TLR3 binds specifically double-strand RNAs (dsRNAs), leading to the activation of mainly two downstream pathways: the phosphorylation of IRF3, with subsequent production of type I interferon, and the activation of NF-κB, which drives the production of inflammatory cytokines and chemokines. Several studies have demonstrated TLR3 expression in multiple neoplasia types including breast, prostate, and lung cancer. Most studies were focused on the beneficial role of TLR3 activation in tumor cells, which leads to the production of cytotoxic cytokines and interferons and promotes caspase-dependent apoptosis. Indeed, ligands of this receptor were proposed for the treatment of cancer, also in combination with conventional chemotherapy. In contrast to these findings, recent evidence showed a link between TLR3 and tumor progression, metastasis, and therapy resistance. In the present review, we summarize the current knowledge of the mechanisms through which TLR3 can either lead to tumor regression or promote carcinogenesis as well as the potential of TLR-based therapies in resistant cancer.
    Keywords:  cytokines; dsRNA; metastasis; therapy resistance; toll-like receptor 3
    DOI:  https://doi.org/10.3390/cancers12113227
  9. Cell Rep. 2020 Nov 03. pii: S2211-1247(20)31330-9. [Epub ahead of print]33(5): 108341
    Mabe NW, Garcia NMG, Wolery SE, Newcomb R, Meingasner RC, Vilona BA, Lupo R, Lin CC, Chi JT, Alvarez JV.
      Dysregulated gene expression is a common feature of cancer and may underlie some aspects of tumor progression, including tumor relapse. Here, we show that recurrent mammary tumors exhibit global changes in gene expression and histone modifications and acquire dependence on the G9a histone methyltransferase. Genetic ablation of G9a delays tumor recurrence, and pharmacologic inhibition of G9a slows the growth of recurrent tumors. Mechanistically, G9a activity is required to silence pro-inflammatory cytokines, including tumor necrosis factor (TNF), through H3K9 methylation at gene promoters. G9a inhibition induces re-expression of these cytokines, leading to p53 activation and necroptosis. Recurrent tumors upregulate receptor interacting protein kinase-3 (RIPK3) expression and are dependent upon RIPK3 activity. High RIPK3 expression renders recurrent tumors sensitive to necroptosis following G9a inhibition. These findings demonstrate that G9a-mediated silencing of pro-necroptotic proteins is a critical step in tumor recurrence and suggest that G9a is a targetable dependency in recurrent breast cancer.
    Keywords:  G9a; RIPK3; breast cancer; collateral sensitivity; epigenetics; necroptosis; recurrence
    DOI:  https://doi.org/10.1016/j.celrep.2020.108341
  10. Cancer Discov. 2020 Nov 02.
    Fendt SM, Frezza C, Erez A.
      Cancer cells continuously rewire their metabolism to fulfill their need for rapid growth and survival while subject to changes in environmental cues. Thus, a vital component of a cancer cell lies in its metabolic adaptability. The constant demand for metabolic alterations requires flexibility, that is, the ability to utilize different metabolic substrates; as well as plasticity, that is, the ability to process metabolic substrates in different ways. In this review, we discuss how dynamic changes in cancer metabolism affect tumor progression and the consequential implications for cancer therapy. SIGNIFICANCE: Recognizing cancer dynamic metabolic adaptability as an entity can lead to targeted therapy that is expected to decrease drug resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0844
  11. Cancer Cell. 2020 Oct 26. pii: S1535-6108(20)30539-0. [Epub ahead of print]
    Zhao W, Li J, Chen MM, Luo Y, Ju Z, Nesser NK, Johnson-Camacho K, Boniface CT, Lawrence Y, Pande NT, Davies MA, Herlyn M, Muranen T, Zervantonakis IK, von Euw E, Schultz A, Kumar SV, Korkut A, Spellman PT, Akbani R, Slamon DJ, Gray JW, Brugge JS, Lu Y, Mills GB, Liang H.
      Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, large-scale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of ∼210 clinically relevant proteins in >12,000 cancer cell line samples in response to ∼170 drug compounds using reverse-phase protein arrays. We show that integrating perturbed protein response signals provides mechanistic insights into drug resistance, increases the predictive power for drug sensitivity, and helps identify effective drug combinations. We build a systematic map of "protein-drug" connectivity and develop a user-friendly data portal for community use. Our study provides a rich resource to investigate the behaviors of cancer cells and the dependencies of treatment responses, thereby enabling a broad range of biomedical applications.
    Keywords:  biomarker; cancer signaling pathway; drug response; protein array
    DOI:  https://doi.org/10.1016/j.ccell.2020.10.008
  12. Nat Commun. 2020 11 03. 11(1): 5549
    Cyrta J, Augspach A, De Filippo MR, Prandi D, Thienger P, Benelli M, Cooley V, Bareja R, Wilkes D, Chae SS, Cavaliere P, Dephoure N, Uldry AC, Lagache SB, Roma L, Cohen S, Jaquet M, Brandt LP, Alshalalfa M, Puca L, Sboner A, Feng F, Wang S, Beltran H, Lotan T, Spahn M, Kruithof-de Julio M, Chen Y, Ballman KV, Demichelis F, Piscuoglio S, Rubin MA.
      Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10-20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors.
    DOI:  https://doi.org/10.1038/s41467-020-19328-1
  13. Cancer Discov. 2020 Nov 06.
      Myeloid cells of the central nervous system expressed a cytokine that suppressed antitumor immunity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-161
  14. Clin Cancer Res. 2020 Nov 04. pii: clincanres.1610.2020. [Epub ahead of print]
    Aggen DH, Ager CR, Obradovic AZ, Chowdhury N, Ghasemzadeh A, Mao W, Chaimowitz MG, Lopez-Bujanda ZA, Spina CS, Hawley JE, Dallos M, Zhang C, Wang V, Li H, Guo XV, Drake CG.
      PURPOSE: Intratumoral immunosuppression mediated by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) represents a potential mechanism of immune checkpoint inhibitor (ICI) resistance in solid tumors. By promoting TAM and MDSC infiltration, Interleukin-1 beta (IL-1b) may drive adaptive and innate immune resistance in renal cell carcinoma (RCC) and in other tumor types.EXPERIMENTAL DESIGN: Using the RENCA model of RCC, we evaluated clinically relevant combinations of anti-IL-1b plus either anti-PD-1 or the multi-targeted tyrosine kinase inhibitor (TKI) cabozantinib. We performed comprehensive immune profiling of established RENCA tumors by via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA sequencing. Similar analyses were extended to the MC38 tumor model.
    RESULTS: Analyses via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA sequencing showed that anti-IL-1b reduces infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and tumor-associated macrophages (TAMs). Combination treatment with anti-IL-1b plus anti-PD-1 or cabozantinib showed increased anti-tumor activity that was associated with decreases in immunosuppressive MDSC and increases in M1-like TAM.
    CONCLUSION/DISCUSSION: Single-cell RNA sequencing analyses show that IL-1b blockade and ICI or TKI remodel the myeloid compartment through non-redundant, relatively T cell independent mechanisms. IL-1b is an upstream mediator of adaptive myeloid resistance and represents a potential target for kidney cancer immunotherapy.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-1610
  15. Cancer Res. 2020 Nov 04. pii: canres.0696.2020. [Epub ahead of print]
    Chen F, Ding K, Priedigkeit N, Elangovan A, Levine KM, Carleton N, Savariau L, Atkinson JM, Oesterreich S, Lee AV.
      Invasive lobular breast carcinoma (ILC), one of the major breast cancer histological subtypes, exhibits unique features compared to the well-studied ductal cancer subtype (IDC). The pathognomonic feature of ILC is loss of E-cadherin, mainly caused by inactivating mutations, but the contribution of this genetic alteration to ILC-specific molecular characteristics remains largely understudied. To profile these features transcriptionally, we conducted single-cell-RNA-sequencing on a panel of IDC and ILC cell lines, and an IDC cell line (T47D) with CRISPR-Cas9-mediated E-cadherin knock out (KO). Inspection of intra-cell line heterogeneity illustrated genetically and transcriptionally distinct subpopulations in multiple cell lines and highlighted rare populations of MCF7 cells highly expressing an apoptosis-related signature, positively correlated with a pre-adaptation signature to estrogen deprivation. Investigation of E-cadherin KO-induced alterations showed transcriptomic membranous systems remodeling, elevated resemblance to ILCs in regulon activation, and increased sensitivity to IFN-γ mediated growth inhibition via activation of IRF1. This study reveals single cell transcriptional heterogeneity in breast cancer cell lines and provides a resource to identify drivers of cancer progression and drug resistance.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0696
  16. Cell Stem Cell. 2020 Nov 05. pii: S1934-5909(20)30501-4. [Epub ahead of print]27(5): 693-695
    Zhang TY, Majeti R.
      Most patients with AML succumb to chemoresistant leukemia stem cells (LSCs), which persist and reinitiate disease years after clinical remission. In this issue of Cell Stem Cell, Jones et al. (2020) identify a therapeutically targetable mechanism of resistance to venetoclax in relapsed and refractory AML LSCs mediated by nicotinamide metabolism.
    DOI:  https://doi.org/10.1016/j.stem.2020.10.007
  17. Cancer Res. 2020 Nov 01. 80(21): 4610-4611
    Nephew KP.
      The study by Gonda and colleagues, in this issue of Cancer Research, represents the first combinatorial approach based on epigenetic therapy priming to overcome resistance to immunotherapy in pancreatic cancer. The authors show that treatment with a DNA hypomethylating agent causes profound changes in the pancreatic cancer microenvironment, including increased numbers of tumor-infiltrating T cells, elevated IFN signaling, and immune checkpoint expression, as well as increased antigen presentation in tumor cells. Accordingly, they show that the combination of decitabine plus immune checkpoint blockade effectively restores antitumor immunity and results in a significant survival benefit in a widely accepted mouse model of pancreatic cancer. The study provides evidence for a new therapeutic approach for pancreatic cancer having antitumor efficacy through modulation of the immune suppressive microenvironment, leading to an increased response to immune checkpoint inhibitors. As the incidence of pancreatic cancer continues to increase, new treatment strategies for this devastating disease are urgently needed. Gonda and colleagues provide preclinical proof of concept for a new therapeutic strategy and address an unmet need for this difficult to treat disease.See related article by Gonda et al., p. 4754.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3097
  18. J Clin Invest. 2020 Nov 05. pii: 135038. [Epub ahead of print]
    Sehgal K, Portell AJ, Ivanova EV, Lizotte PH, Mahadevan NR, Greene JR, Vajdi A, Gurjao C, Teceno T, Taus LJ, Thai TC, Kitajima S, Liu D, Tani T, Noureddine M, Lau CJ, Kirschmeier PT, Liu D, Giannakis M, Jenkins RW, Gokhale PC, Goldoni S, Pinzon-Ortiz M, Hastings WD, Hammerman P, Miret JJ, Paweletz CP, Barbie DA.
      Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed death (PD)-1 blockade is poorly understood. Here, we performed dynamic single-cell RNA sequencing of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete sub-population of immunotherapy persister cells (IPCs) that resisted CD8 T-cell mediated killing. These cells expressed Snai1 and stem cell antigen-1 (Sca-1), and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by interleukin-6 (IL-6) but were vulnerable to tumor necrosis factor-alpha (TNF-α)-induced cytotoxicity, relying on Birc2 and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.
    Keywords:  Apoptosis survival pathways; Cancer immunotherapy; Cellular immune response; Immunology; Oncology
    DOI:  https://doi.org/10.1172/JCI135038
  19. Mol Cell. 2020 Nov 05. pii: S1097-2765(20)30718-8. [Epub ahead of print]80(3): 377-378
    Caeser R, Sen T.
      Li et al. (2020) elucidate the resistance mechanisms to small-molecule inhibitors targeting the G2/M cell cycle checkpoint kinase, CHK1, in a variety of non-small cell lung cancer cell lines using CRISPR-mediated genetic approaches and identify biomarkers of response.
    DOI:  https://doi.org/10.1016/j.molcel.2020.10.011
  20. Proc Natl Acad Sci U S A. 2020 Nov 03. pii: 202016067. [Epub ahead of print]
    Vassel FM, Bian K, Walker GC, Hemann MT.
      Cisplatin is a standard of care for lung cancer, yet platinum therapy rarely results in substantial tumor regression or a dramatic extension in patient survival. Here, we examined whether targeting Rev7 (also referred to as Mad2B, Mad2L2, and FANCV), a component of the translesion synthesis (TLS) machinery, could potentiate the action of cisplatin in non-small cell lung cancer (NSCLC) treatment. Rev7 loss led to an enhanced tumor cell sensitivity to cisplatin and dramatically improved chemotherapeutic response in a highly drug-resistant mouse model of NSCLC. While cisplatin monotherapy resulted in tumor cell apoptosis, Rev7 deletion promoted a cisplatin-induced senescence phenotype. Moreover, Rev7 deficiency promoted greater cisplatin sensitivity than that previously shown following targeting of other Pol ζ-proteins, suggesting that Pol ζ-dependent and -independent roles of Rev7 are relevant to cisplatin response. Thus, targeting Rev7 may represent a unique strategy for altering and enhancing chemotherapeutic response.
    Keywords:  Rev7; chemotherapy; cisplatin; lung cancer; translesion synthesis
    DOI:  https://doi.org/10.1073/pnas.2016067117
  21. PLoS Genet. 2020 Nov 02. 16(11): e1009176
    Schleicher EM, Dhoonmoon A, Jackson LM, Clements KE, Stump CL, Nicolae CM, Moldovan GL.
      The ataxia telangiectasia and Rad3-related (ATR) protein kinase is a key regulator of the cellular response to DNA damage. Due to increased amount of replication stress, cancer cells heavily rely on ATR to complete DNA replication and cell cycle progression. Thus, ATR inhibition is an emerging target in cancer therapy, with multiple ATR inhibitors currently undergoing clinical trials. Here, we describe dual genome-wide CRISPR knockout and CRISPR activation screens employed to comprehensively identify genes that regulate the cellular resistance to ATR inhibitors. Specifically, we investigated two different ATR inhibitors, namely VE822 and AZD6738, in both HeLa and MCF10A cells. We identified and validated multiple genes that alter the resistance to ATR inhibitors. Importantly, we show that the mechanisms of resistance employed by these genes are varied, and include restoring DNA replication fork progression, and prevention of ATR inhibitor-induced apoptosis. In particular, we describe a role for MED12-mediated inhibition of the TGFβ signaling pathway in regulating replication fork stability and cellular survival upon ATR inhibition. Our dual genome-wide screen findings pave the way for personalized medicine by identifying potential biomarkers for ATR inhibitor resistance.
    DOI:  https://doi.org/10.1371/journal.pgen.1009176
  22. Clin Cancer Res. 2020 Nov 04. pii: clincanres.1900.2020. [Epub ahead of print]
    Tsang ES, Grisdale CJ, Pleasance ED, Topham JT, Mungall KL, Reisle CR, Choo C, Carreira M, Bowlby R, Karasinska JM, MacMillan D, Williamson LM, Chuah E, Moore RA, Mungall AJ, Zhao Y, Tessier-Cloutier B, Ng T, Sun S, Lim H, Schaeffer DF, Renouf DJ, Yip S, Laskin J, Marra MA, Jones SJ, Loree JM.
      PURPOSE: Gene fusions are important oncogenic drivers and many are actionable. Whole genome and transcriptome (WGS and RNA-Seq, respectively) sequencing can discover novel clinically relevant fusions.EXPERIMENTAL DESIGN: Using WGS and RNA-Seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches.
    RESULTS: In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-Seq, of which 18 fusions by WGS and 19 by RNA-Seq were noted in at least three separate patients. The most common fusions were EML4-ALK in thoracic malignancies (9/69, 13%), and CMTM8-CMTM7 in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as NTRK2 (novel partners: SHC3, DAPK1), and NTRK3 (novel partners: POLG, PIBF1).
    CONCLUSIONS: Utilizing WGS/RNA-Seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-Seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-1900
  23. Cancer Metastasis Rev. 2020 Nov 02.
    van Loon K, Huijbers EJM, Griffioen AW.
      Secreted frizzled-related proteins (SFRP) are glycoproteins containing a so-called frizzled-like cysteine-rich domain. This domain enables them to bind to Wnt ligands or frizzled (FzD) receptors, making potent regulators of Wnt signaling. As Wnt signaling is often altered in cancer, it is not surprising that Wnt regulators such as SFRP proteins are often differentially expressed in the tumor microenvironment, both in a metastatic and non-metastatic setting. Indeed, SFRP2 is shown to be specifically upregulated in the tumor vasculature of several types of cancer. Several studies investigated the functional role of SFRP2 in the tumor vasculature, showing that SFRP2 binds to FzD receptors on the surface of tumor endothelial cells. This activates downstream Wnt signaling and which is, thereby, stimulating angiogenesis. Interestingly, not the well-known canonical Wnt signaling pathway, but the noncanonical Wnt/Ca2+ pathway seems to be a key player in this event. In tumor models, the pro-angiogenic effect of SFRP2 could be counteracted by antibodies targeting SFRP2, without the occurrence of toxicity. Since tumor angiogenesis is an important process in tumorigenesis and metastasis formation, specific tumor endothelial markers such as SFRP2 show great promise as targets for anti-cancer therapies. This review discusses the role of SFRP2 in noncanonical Wnt signaling and tumor angiogenesis, and highlights its potential as anti-angiogenic therapeutic target in cancer.
    Keywords:  Angiogenesis; Cancer; SFRP2; Therapeutic target; Tumor vasculature; Wnt signaling
    DOI:  https://doi.org/10.1007/s10555-020-09941-3