bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒07‒25
twenty papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma.
  2. Metabolic mechanisms of medulloblastoma metastasis.
  3. Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy.
  4. Understanding and overcoming resistance to PARP inhibitors in cancer therapy.
  5. Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer.
  6. Lentiviral-driven discovery of cancer drug resistance mutations.
  7. miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts.
  8. Targeting c-Myc to overcome acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR tyrosine kinase inhibitor, osimertinib.
  9. A Chemokine Regulatory Loop Induces Cholesterol Synthesis in Lung-Colonizing Triple-Negative Breast Cancer Cells to Fuel Metastatic Growth.
  10. Oncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis.
  11. Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING.
  12. Optineurin Guards IFNγ Signaling in Cancer Cells.
  13. KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.
  14. CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma.
  15. Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer.
  16. Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma.
  17. Structures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism.
  18. Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis.
  19. The ELF3-regulated lncRNA UBE2CP3 is over-stabilized by RNA-RNA interactions and drives gastric cancer metastasis via miR-138-5p/ITGA2 axis.
  20. Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA.
  1. J Exp Med. 2021 Sep 06. pii: e20210571. [Epub ahead of print]218(9):
    Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma.
    Roberto Vendramin, Vicky Katopodi, Sonia Cinque, Angelina Konnova, Zorica Knezevic, Sara Adnane, Yvessa Verheyden, Panagiotis Karras, Ewout Demesmaeker, Francesca M Bosisio, Lukas Kucera, Jan Rozman, Ivan Gladwyn-Ng, Lara Rizzotto, Erik Dassi, Stefania Millevoi, Oliver Bechter, Jean-Christophe Marine, Eleonora Leucci.
      The ability to adapt to environmental stress, including therapeutic insult, contributes to tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by dampening cytosolic translation. We show that ISR-dependent survival also relies on a concomitant up-regulation of mitochondrial protein synthesis, a vulnerability that can be exploited using mitoribosome-targeting antibiotics. Accordingly, such agents sensitized to MAPK inhibition, thus preventing the development of resistance in BRAFV600E melanoma models. Additionally, this treatment compromised the growth of melanomas that exhibited elevated ISR activity and resistance to both immunotherapy and targeted therapy. In keeping with this, pharmacological inactivation of ISR, or silencing of ATF4, rescued the antitumoral response to the tetracyclines. Moreover, a melanoma patient exposed to doxycycline experienced complete and long-lasting response of a treatment-resistant lesion. Our study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy in BRAF mutant melanoma and a therapeutic option for NRAS-driven and immunotherapy-resistant tumors.
    DOI:  https://doi.org/10.1084/jem.20210571
  2. Nat Rev Cancer. 2021 Jul 19.
    Metabolic mechanisms of medulloblastoma metastasis.
    Sarah Seton-Rogers.
      
    DOI:  https://doi.org/10.1038/s41568-021-00391-9
  3. Cell Rep. 2021 Jul 20. pii: S2211-1247(21)00823-8. [Epub ahead of print]36(3): 109410
    Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy.
    Christopher J Terranova, Ming Tang, Mayinuer Maitituoheti, Ayush T Raman, Archit K Ghosh, Jonathan Schulz, Samir B Amin, Elias Orouji, Katarzyna Tomczak, Sharmistha Sarkar, Junna Oba, Caitlin Creasy, Chang-Jiun Wu, Samia Khan, Rossana Lazcano, Khalida Wani, Anand Singh, Praveen Barrodia, Dongyu Zhao, Kaifu Chen, Lauren E Haydu, Wei-Lien Wang, Alexander J Lazar, Scott E Woodman, Chantale Bernatchez, Kunal Rai.
      The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients.
    Keywords:  Polycomb repressive complex 2; bivalent; broad domains; chromatin; epigenetics; melanoma; melanoma therapeutics; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2021.109410
  4. Nat Rev Clin Oncol. 2021 Jul 20.
    Understanding and overcoming resistance to PARP inhibitors in cancer therapy.
    Mariana Paes Dias, Sarah C Moser, Shridar Ganesan, Jos Jonkers.
      Developing novel targeted anticancer therapies is a major goal of current research. The use of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with homologous recombination-deficient tumours provides one of the best examples of a targeted therapy that has been successfully translated into the clinic. The success of this approach has so far led to the approval of four different PARP inhibitors for the treatment of several types of cancers and a total of seven different compounds are currently under clinical investigation for various indications. Clinical trials have demonstrated promising response rates among patients receiving PARP inhibitors, although the majority will inevitably develop resistance. Preclinical and clinical data have revealed multiple mechanisms of resistance and current efforts are focused on developing strategies to address this challenge. In this Review, we summarize the diverse processes underlying resistance to PARP inhibitors and discuss the potential strategies that might overcome these mechanisms such as combinations with chemotherapies, targeting the acquired vulnerabilities associated with resistance to PARP inhibitors or suppressing genomic instability.
    DOI:  https://doi.org/10.1038/s41571-021-00532-x
  5. Nat Commun. 2021 07 21. 12(1): 4441
    Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer.
    Wenyu Wang, Yen-An Tang, Qian Xiao, Wee Chyan Lee, Bing Cheng, Zhitong Niu, Gokce Oguz, Min Feng, Puay Leng Lee, Baojie Li, Zi-Huan Yang, Yu-Feng Chen, Ping Lan, Xiao-Jian Wu, Qiang Yu.
      BRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively.
    DOI:  https://doi.org/10.1038/s41467-021-24687-4
  6. Cancer Res. 2021 Jul 23. pii: canres.1153.2021. [Epub ahead of print]
    Lentiviral-driven discovery of cancer drug resistance mutations.
    Paul Yenerall, Rahul K Kollipara, Kimberley Avila, Michael Peyton, Christopher A Eide, Daniel Bottomly, Shannon K McWeeney, Yan Liu, Kenneth D Westover, Brian J Druker, John D Minna, Ralf Kittler.
      Identifying resistance mutations in a drug target provides crucial information. Lentiviral transduction creates multiple types of mutations due to the error-prone nature of the HIV-1 reverse transcriptase (RT). Here we optimized and leveraged this property to identify drug resistance mutations, developing a technique we term LentiMutate. This technique was validated by identifying clinically relevant EGFR resistance mutations, then applied to two additional clinical anti-cancer drugs: imatinib, a BCR-ABL inhibitor, and AMG 510, a KRAS G12C inhibitor. Novel deletions in BCR-ABL1 conferred resistance to imatinib. In KRAS-G12C or wild-type KRAS, point mutations in the AMG 510 binding pocket or oncogenic non-G12C mutations conferred resistance to AMG 510. LentiMutate should prove highly valuable for clinical and preclinical cancer drug development.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1153
  7. Genes Dev. 2021 Jul 22.
    miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts.
    Bin Xue, Chen-Hua Chuang, Haydn M Prosser, Cesar Seigi Fuziwara, Claudia Chan, Neil Sahasrabudhe, Maximilian Kühn, Yalei Wu, Jingqi Chen, Anne Biton, Caifu Chen, John Erby Wilkinson, Michael T McManus, Allan Bradley, Monte M Winslow, Bo Su, Lin He.
      Lung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identified miR-200 miRNAs as potent suppressors for lung adenocarcinoma metastasis. miR-200 expression is specifically repressed in mouse metastatic lung adenocarcinomas, and miR-200 decrease strongly correlates with poor patient survival. Consistently, deletion of mir-200c/141 in the Kras LSL-G12D/+ ; Trp53 flox/flox lung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer. miR-200 deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells. miR-200 regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential.
    Keywords:  Jag1; Jag2; cancer-associated fibroblasts; lung cancer; metastasis; miR-141; miR-200; miR-200c; miRNA; microenvironment
    DOI:  https://doi.org/10.1101/gad.347344.120
  8. Cancer Res. 2021 Jul 21. pii: canres.0556.2021. [Epub ahead of print]
    Targeting c-Myc to overcome acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR tyrosine kinase inhibitor, osimertinib.
    Lei Zhu, Zhen Chen, Hongjing Zang, Songqing Fan, Jiajia Gu, Guojing Zhang, Kevin D-Y Sun, Qiming Wang, Yong He, Taofeek K Owonikoko, Suresh S Ramalingam, Shi-Yong Sun.
      Osimertinib (AZD9291 or TAGRISSOTM) is a promising and approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treating patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations or the resistant T790M mutation. However, the inevitable emergence of acquired resistance limits its long-term efficacy. A fuller understanding of the mechanism of action of osimertinib and its linkage to acquired resistance will enable the development of more efficacious therapeutic strategies. Consequently, we have identified a novel connection between osimertinib or other EGFR TKI and c-Myc. Osimertinib rapidly and sustainably decreased c-Myc levels primarily via enhancing protein degradation in EGFR-mutant (EGFRm) NSCLC cell lines and xenograft tumors. c-Myc levels were substantially elevated in different EGFRm NSCLC cell lines with acquired resistance to osimertinib in comparison with their corresponding parental cell lines and could not be reduced any further by osimertinib. Consistently, c-Myc levels were elevated in the majority of EGFRm NSCLC tissues relapsed from EGFR-TKI treatment compared to their corresponding untreated baseline c-Myc levels. Suppression of c-Myc through knockdown or pharmacological targeting with BET inhibitors restored the response of resistant cell lines to osimertinib. These findings indicate that c-Myc modulation mediates the therapeutic efficacy of osimertinib and the development of osimertinib-acquired resistance. Furthermore, they establish c-Myc as a potential therapeutic target and warrant clinical testing of BET inhibition as a potential strategy to overcome acquired resistance to osimertinib or other EGFR inhibitors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0556
  9. Mol Ther. 2021 Jul 15. pii: S1525-0016(21)00357-9. [Epub ahead of print]
    A Chemokine Regulatory Loop Induces Cholesterol Synthesis in Lung-Colonizing Triple-Negative Breast Cancer Cells to Fuel Metastatic Growth.
    Bingchen Han, Felix Alonso-Valenteen, Zhe Wang, Nan Deng, Tian-Yu Lee, Bowen Gao, Ying Zhang, Yali Xu, Xinfeng Zhang, Sandrine Billet, Xuemo Fan, Stephen Shiao, Neil Bhowmick, Lali Medina-Kauwe, Armando Giuliano, Xiaojiang Cui.
      Triple-negative breast cancer (TNBC) has a high propensity for organ-specific metastasis. However, the underlying mechanisms are not well understood. Here, we show that the primary TNBC tumor-derived C-X-C motif chemokines 1/2/8 (CXCL1/2/8) stimulate lung resident fibroblasts to produce C-C motif chemokines 2/7 (CCL2/7), which in turn activate cholesterol synthesis in lung-colonizing TNBC cells and induce angiogenesis at lung metastatic sites. Inhibiting cholesterol synthesis in lung-colonizing breast tumor cells by the pulmonary administration of simvastatin-carrying HER3-targeting nanoparticles reduces the angiogenesis and growth of lung metastases in a syngeneic TNBC mouse model. Our findings reveal a novel, chemokine-regulated mechanism for the cholesterol synthesis pathway and a critical role of metastatic site-specific cholesterol synthesis in the pulmonary tropism of TNBC metastasis. The study has implications for the unresolved epidemiological observation that the use of cholesterol-lowering drugs has no effect on breast cancer incidence but can unexpectedly reduce breast cancer mortality, suggesting interventions of cholesterol synthesis in lung metastases as an effective treatment to improve survival in TNBC patients.
    Keywords:  Chemokine; Cholesterol; Lung fibroblasts; Lung metastasis; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.ymthe.2021.07.003
  10. Nat Commun. 2021 07 22. 12(1): 4457
    Oncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis.
    Bo Ye, Dandan Fan, Weiwei Xiong, Min Li, Jian Yuan, Qi Jiang, Yuting Zhao, Jianxiang Lin, Jie Liu, Yilv Lv, Xiongjun Wang, Zhigang Li, Jianzhong Su, Yunbo Qiao.
      The role of cis-elements and their aberrations remains unclear in esophageal squamous cell carcinoma (ESCC, further abbreviated EC). Here we survey 28 H3K27ac-marked active enhancer profiles and 50 transcriptomes in primary EC, metastatic lymph node cancer (LNC), and adjacent normal (Nor) esophageal tissues. Thousands of gained or lost enhancers and hundreds of altered putative super-enhancers are identified in EC and LNC samples respectively relative to Nor, with a large number of common gained or lost enhancers. Moreover, these differential enhancers contribute to the transcriptomic aberrations in ECs and LNCs. We also reveal putative driver onco-transcription factors, depletion of which diminishes cell proliferation and migration. The administration of chemical inhibitors to suppress the predicted targets of gained super-enhances reveals HSP90AA1 and PDE4B as potential therapeutic targets for ESCC. Thus, our epigenomic profiling reveals a compendium of reprogrammed cis-regulatory elements during ESCC carcinogenesis and metastasis for uncovering promising targets for cancer treatment.
    DOI:  https://doi.org/10.1038/s41467-021-24813-2
  11. Cell Rep. 2021 Jul 20. pii: S2211-1247(21)00825-1. [Epub ahead of print]36(3): 109412
    Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING.
    Marine Bruand, David Barras, Marco Mina, Eleonora Ghisoni, Matteo Morotti, Evripidis Lanitis, Noémie Fahr, Mathieu Desbuisson, Alizée Grimm, Hualing Zhang, Chloe Chong, Julien Dagher, Sora Chee, Theodora Tsianou, Julien Dorier, Brian J Stevenson, Christian Iseli, Catherine Ronet, Sara Bobisse, Raphael Genolet, Josephine Walton, Michal Bassani-Sternberg, Lana E Kandalaft, Bing Ren, Iain McNeish, Elizabeth Swisher, Alexandre Harari, Mauro Delorenzi, Giovanni Ciriello, Melita Irving, Sylvie Rusakiewicz, Periklis G Foukas, Fabio Martinon, Denarda Dangaj Laniti, George Coukos.
      In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1mut) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1mut cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8+ T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53-/-Brca1-/- but not Brca1+/+ ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers.
    Keywords:  BRCA1; CTLA-4; DNA sensing; ICB; PARPi; PD-L1; STING; T cells; VEGF-A; angiogenesis; dual immune checkpoint blockade; ovarian cancer; type I IFN
    DOI:  https://doi.org/10.1016/j.celrep.2021.109412
  12. Cancer Discov. 2021 Jul;11(7): 1623-1625
    Optineurin Guards IFNγ Signaling in Cancer Cells.
    Camilla Salvagno, Juan R Cubillos-Ruiz.
      In this issue, Du and colleagues uncover that optineurin functions as a key regulator of IFNγ receptor (IFNGR1) stability in malignant cells. Loss of optineurin in colorectal cancer cells causes IFNGR1 degradation, leading to impaired IFNγ signaling, decreased MHC-I expression, and enhanced ability to evade adaptive immune control.See related article by Du et al., p. 1826.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0362
  13. Proc Natl Acad Sci U S A. 2021 Jul 27. pii: e2023112118. [Epub ahead of print]118(30):
    KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.
    Marina Salmón, Guillem Paniagua, Carmen G Lechuga, Fernando Fernández-García, Eduardo Zarzuela, Ruth Álvarez-Díaz, Monica Musteanu, Carmen Guerra, Eduardo Caleiras, Javier Muñoz, Sagrario Ortega, Matthias Drosten, Mariano Barbacid.
      In mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a Kras FSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras +/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras +/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences.
    Keywords:  KRAS isoforms; alternative splicing; gene editing; hypertrabeculation; lung tumors
    DOI:  https://doi.org/10.1073/pnas.2023112118
  14. EMBO Rep. 2021 Jul 23. e51683
    CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma.
    Pietro Berico, Max Cigrang, Guillaume Davidson, Cathy Braun, Jeremy Sandoz, Stephanie Legras, Bujamin Hektor Vokshi, Nevena Slovic, François Peyresaubes, Carlos Mario Gene Robles, Jean-Marc Egly, Emmanuel Compe, Irwin Davidson, Frederic Coin.
      Melanoma cell phenotype switching between differentiated melanocytic and undifferentiated mesenchymal-like states drives metastasis and drug resistance. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We show that dedifferentiation of melanocytic-type melanoma cells into mesenchymal-like cells and acquisition of tolerance to targeted therapies is achieved through chronic inhibition of CDK7. In addition to emergence of a mesenchymal-type signature, we identify a GATA6-dependent gene expression program comprising genes such as AMIGO2 or ABCG2 involved in melanoma survival or targeted drug tolerance, respectively. Mechanistically, we show that CDK7 drives expression of the melanocyte lineage transcription factor MITF that in turn binds to an intronic region of GATA6 to repress its expression in melanocytic-type cells. We show that GATA6 expression is activated in MITF-low melanoma cells of patient-derived xenografts. Taken together, our data show how the poorly characterized repressive function of MITF in melanoma participates in a molecular cascade regulating activation of a transcriptional program involved in survival and drug resistance in melanoma.
    Keywords:  CDK7; GATA6; MITF; TFIIH; melanoma
    DOI:  https://doi.org/10.15252/embr.202051683
  15. Cancer Res. 2021 Jul 23. pii: canres.4028.2020. [Epub ahead of print]
    Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer.
    Asmaa El-Kenawi, William Dominguez-Viqueira, Min Liu, Shivanshu Awasthi, Julieta Abraham-Miranda, Aysenur Keske, KayLee K Steiner, Leenil Noel, Amparo N Serna, Jasreman Dhillon, Robert J Gillies, Xiaoqing Yu, John M Koomen, Kosj Yamoah, Robert A Gatenby, Brian Ruffell.
      Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance. In a syngeneic model that reflected the mutational landscape of CRPC, macrophage depletion resulted in a reduced transcriptional signature for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. As cholesterol is the precursor of the five major types of steroid hormones, we hypothesized that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Macrophage depletion reduced androgen levels within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were also cholesterol-rich and were able to transfer cholesterol to tumor cells in vitro. AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Consistent with these data, macrophage depletion extended survival during ADT and the presence of macrophages correlated with therapeutic resistance in patient-derived explants. Taken together, these findings support the therapeutic targeting of macrophages in CRPC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-4028
  16. Clin Cancer Res. 2021 Jul 20. pii: clincanres.1367.2021. [Epub ahead of print]
    Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma.
    James M Cleary, Brian M Wolpin, Stephanie K Dougan, Srivatsan Raghavan, Harshabad Singh, Brandon Huffman, Nilay S Sethi, Jonathan A Nowak, Geoffrey I Shapiro, Andrew J Aguirre, Alan D D'Andrea.
      Pancreatic cancer is rapidly progressive and notoriously difficult to treat with cytotoxic chemotherapy and targeted agents. Recent demonstration of the efficacy of maintenance PARP inhibition in germline BRCA mutated pancreatic cancer has raised hopes that increased understanding of the DNA damage response pathway will lead to new therapies in both homologous recombination (HR) repair-deficient and proficient pancreatic cancer. Here, we review the potential mechanisms of exploiting HR deficiency, replicative stress, and DNA damage-mediated immune activation through targeted inhibition of DNA repair regulatory proteins.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1367
  17. Nat Commun. 2021 07 19. 12(1): 4376
    Structures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism.
    Qin Yu, Dongchun Ni, Julia Kowal, Ioannis Manolaridis, Scott M Jackson, Henning Stahlberg, Kaspar P Locher.
      ABCG2 is a multidrug transporter that affects drug pharmacokinetics and contributes to multidrug resistance of cancer cells. In previously reported structures, the reaction cycle was halted by the absence of substrates or ATP, mutation of catalytic residues, or the presence of small-molecule inhibitors or inhibitory antibodies. Here we present cryo-EM structures of ABCG2 under turnover conditions containing either the endogenous substrate estrone-3-sulfate or the exogenous substrate topotecan. We find two distinct conformational states in which both the transport substrates and ATP are bound. Whereas the state turnover-1 features more widely separated NBDs and an accessible substrate cavity between the TMDs, turnover-2 features semi-closed NBDs and an almost fully occluded substrate cavity. Substrate size appears to control which turnover state is mainly populated. The conformational changes between turnover-1 and turnover-2 states reveal how ATP binding is linked to the closing of the cytoplasmic side of the TMDs. The transition from turnover-1 to turnover-2 is the likely bottleneck or rate-limiting step of the reaction cycle, where the discrimination of substrates and inhibitors occurs.
    DOI:  https://doi.org/10.1038/s41467-021-24651-2
  18. Cell Stem Cell. 2021 Jul 12. pii: S1934-5909(21)00274-5. [Epub ahead of print]
    Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis.
    Amit Subedi, Qiang Liu, Dhanoop M Ayyathan, David Sharon, Severine Cathelin, Mohsen Hosseini, Changjiang Xu, Veronique Voisin, Gary D Bader, Angelo D'Alessandro, Eric R Lechman, John E Dick, Mark D Minden, Jean C Y Wang, Steven M Chan.
      Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomic analysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-element binding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBP signaling with dipyridamole enhanced the cytotoxicity of KPT-9274 on LSCs in vivo. Our work demonstrates that altered lipid homeostasis plays a key role in NAMPT inhibitor-induced apoptosis and identifies NAMPT inhibition as a therapeutic strategy for targeting LSCs in AML.
    Keywords:  NAD metabolism; NAMPT; SREBP signaling; acute myeloid leukemia; dipyridamole; drug screen; fatty acid; leukemic stem cells; lipotoxicity; metabolism
    DOI:  https://doi.org/10.1016/j.stem.2021.06.004
  19. Oncogene. 2021 Jul 17.
    The ELF3-regulated lncRNA UBE2CP3 is over-stabilized by RNA-RNA interactions and drives gastric cancer metastasis via miR-138-5p/ITGA2 axis.
    Dandan Li, Jiajun She, Xinhui Hu, Meixin Zhang, Ruonan Sun, Shanshan Qin.
      LncRNAs play essential roles in tumorigenesis and tumor progression. Pseudogene UBE2CP3 is an antisense intronic lncRNA. However, the biological function of UBE2CP3 in gastric cancer (GC) remains unknown. In this study, we revealed that lncRNA UBE2CP3 was aberrantly upregulated in multiple independent gastric cancer cohorts, and its overexpression was clinically associated with poor prognosis in GC. UBE2CP3 was mainly located in cytoplasm and promoted migratory and invasive capacities of GC cells in vitro and in vivo. Mechanismly, a novel dysregulated ceRNA network UB2CP3/miR-138-5p/ITGA2 was identified in GC by transcriptome sequencing. Furthermore, rescue assay further confirmed that UBE2CP3 mainly promoted GC progression through miR-138-5p/ITGA2 axis. More importantly, our data proved that UBE2CP3/IGFBP7 could form an RNA duplex, thereby directly interacting with the ILF3 protein. In turn, this RNA-RNA interaction between IGFBP7 mRNA and UBE2CP3 mediated by ILF3 protein plays an essential role in protecting the mRNA stability of UBE2CP3. In addition, transcription factor ELF3 was identified to be a direct repressor of lncRNA UBE2CP3 in GC. Taken together, overexpression of UBE2CP3 promotes tumor progression via cascade amplification of ITGA2 upregulation in GC. Our finding has revealed that the dysregulation of UBE2CP3 is probably due to the downregulation of ELF3 and/or the overexpression of IGFBP7 mRNA in GC. Our findings reveal, for the first time, that UBE2CP3 plays crucial a role in GC progression by modulating miR-138-5p/ITGA2 axis, suggesting that UBE2CP3 may serve as a potential therapeutic target in GC.
    DOI:  https://doi.org/10.1038/s41388-021-01948-6
  20. Nat Biotechnol. 2021 Jul 22.
    Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA.
    David M Kurtz, Joanne Soo, Lyron Co Ting Keh, Stefan Alig, Jacob J Chabon, Brian J Sworder, Andre Schultz, Michael C Jin, Florian Scherer, Andrea Garofalo, Charles W Macaulay, Emily G Hamilton, Binbin Chen, Mari Olsen, Joseph G Schroers-Martin, Alexander F M Craig, Everett J Moding, Mohammad S Esfahani, Chih Long Liu, Ulrich Dührsen, Andreas Hüttmann, René-Olivier Casasnovas, Jason R Westin, Mark Roschewski, Wyndham H Wilson, Gianluca Gaidano, Davide Rossi, Maximilian Diehn, Ash A Alizadeh.
      Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.
    DOI:  https://doi.org/10.1038/s41587-021-00981-w
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