Molecular and Cellular Biology / Genetics最新文献

{"title":"Abstract 2052: TRIP13 amplification confers PARP inhibitor resistance and polymerase theta inhibitor sensitivity","authors":"Jeffrey Patterson-Fortin, Jia Zhou, A. D’Andrea","doi":"10.1158/1538-7445.AM2021-2052","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2052","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"125 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73724504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1986: p53/FBXL20 axis negatively regulates the protein stability of PR55α, a PP2A regulatory subunit","authors":"Ying Yan, Lepakshe S V Madduri, Nichole D. Brandquist, C. Palanivel, Sumin Zhou, C. Enke, M. Ouellette","doi":"10.1158/1538-7445.AM2021-1986","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1986","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74659241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2012:In vitrovalidation of tumor-derived large extracellular vesicles isolation and characterization as suitable tool for liquid biopsy","authors":"G. Pezzicoli, D. Lovero, M. Tucci, C. Porta, Francesco Mannavola","doi":"10.1158/1538-7445.AM2021-2012","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2012","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74670958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2507: Does a threshold exist for NRF2 hyperactivation to block tumor progression in KRAS mutant, TP53-deficient NSCLC","authors":"Janine Deblasi, Aimee Falzone, G. DeNicola","doi":"10.1158/1538-7445.AM2021-2507","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2507","url":null,"abstract":"Lung cancer is responsible for the most cancer-related deaths worldwide. Within the most prominent histological subtype, non-small cell lung cancer (NSCLC), there is an unmet clinical need: lung adenocarcinomas (ADCs) driven by mutant KRAS. Within this subset of tumors, KRAS mutations co-occur with mutations in tumor suppressor genes including TP53 and the redox regulator KEAP1. KEAP1 is the negative regulator of transcription factor NRF2, which directs the antioxidant response and multiple facets of metabolism. In NSCLC, alterations in the KEAP1-NRF2 circuit result in constitutive NRF2 activation and are often associated with resistance to therapy and poor outcomes in patients. While NRF2 hyperactivation has been associated with tumor progression, our lab's recent findings suggest that this may be context-dependent, and that too much NRF2 activation may be detrimental. To study the role of NRF2 hyperactivation on tumor progression, we have utilized KRAS mutant genetically engineered mouse models of NSCLC harboring TP53 deletion. These studies are based on our lab's finding that the homozygous KEAP1R554Q loss-of-function mutation decreases tumor size in a Kras mutant, Trp53-deficient (KP) lung ADC model (Kang et al. 2019 eLife). In parallel to these studies, we have also developed a conditional murine allele of the NRF2D29H mutation found in human NSCLC to serve as a secondary model of NRF2 hyperactivation in the KP mouse (KPN). Consistent with our homozygous KEAP1 mutant model (KPKK), we found that KPN mice demonstrated constitutive NRF2 activation, as observed by increased immunohistochemical staining of canonical NRF2 target, NQO1. This degree of NRF2 activation in KPN mice was slightly lower than that of KPKK mice, suggesting that the KPN mouse is an intermediate model of NRF2 activation. Supportingly, we also found that KPN mice had decreased tumor burden, although not to the same extent as KPKK mice. Interestingly, our heterozygous KEAP1 mutant model (KPK) demonstrates only modest NRF2 activation but did not exhibit decreased tumor burden. Importantly, analyses of tumor number suggested that KPKK and KPN tumors are impaired in tumor progression, rather than initiation. KPKK and KPN tumors also exhibited lower proliferative indices when compared to KP mice, in correspondence with their reduced tumor burden. Collectively, these results suggest that there may be a threshold for NRF2 activation to block tumor progression in the KP model. Current studies are focused on determining whether this impediment to tumor burden is NRF2-dependent, and what NRF2-dependent mechanisms may impair tumor progression. Importantly, these studies may help identify whether a threshold for NRF2 hyperactivation to promote or block tumor progression exists, and if this can be therapeutically exploited in patients with KRAS mutant, TP53-deficient lung tumors. Citation Format: Janine M. DeBlasi, Aimee Falzone, Gina M. DeNicola. Does a threshold exist for NRF2 hyperacti","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74886016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2481: Time-resolved transcriptome analysis of murine TH-MYCN driven neuroblastoma identifies MEIS2 as early initiating factor and novel core gene regulatory circuitry constituent","authors":"K. Durinck, Mark W. Zimmerman, Nina Weichert-Leahey, J. Dewyn, W. V. Loocke, C. Nunes, A. Beckers, Bieke Decaesteker, P. Volders, C. V. Neste, B. Cheung, Daniel R. Carter, T. Look, G. Marshall, K. D. Preter, Adam D. Durbin, F. Speleman","doi":"10.1158/1538-7445.AM2021-2481","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2481","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"133 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75696371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2185: Genetic analysis of metachronous pancreatic cancers","authors":"Tomonori Hirano, N. Kakiuchi, Y. Takeuchi, T. Nishimura, T. Masui, Sachiko Minamiguhi, H. Haga, K. Chiba, Hiroko Tanaka, Y. Shiraishi, S. Miyano, Uza Norimitsu, Y. Kodama, H. Seno, S. Ogawa","doi":"10.1158/1538-7445.AM2021-2185","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2185","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74040124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1962: Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models","authors":"S. Wiley, Yongwei Su, Y. Ge","doi":"10.1158/1538-7445.AM2021-1962","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1962","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75106498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 91: FLT3 is a major driver of glucose consumption in squamous cell lung cancer","authors":"C. Ghezzi, R. Damoiseaux, P. M. Clark","doi":"10.1158/1538-7445.AM2021-91","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-91","url":null,"abstract":"Squamous cell lung cancer (SqCLC) represents 30% of all cases of non-small cell lung cancer. Despite the prevalence of SqCLC, there are few molecularly targeted therapies for SqCLC patients. There is an urgent need for new approaches in this area. SqCLC cells consume elevated levels of glucose and are highly dependent on glucose consumption for their survival. Targeting glucose consumption may be a valuable therapeutic strategy in SqCLC but is challenged by the fact that glucose consumption is critical for vital organs. Our ability to selectively target glucose consumption in SqCLC is limited by an incomplete understanding of the shared and distinct mechanisms through which SqCLC and healthy cells drive glucose consumption. We recently developed and validated a high-throughput glucose consumption assay that serves as a platform technology for identifying new proteins and pathways that drive glucose consumption in cancerous and healthy cells. In this project, we screened H520, SK-MES-1, and H596 SqCLC cell lines against 3555 bioactive small molecules including a library of kinase inhibitors and FDA-approved drugs, and measured glucose consumption 24 hours after drug treatment. We discovered and validated 62 compounds that decreased glucose consumption per cell by >50% in at least one cell line. From this list, we searched for compounds that decreased glucose consumption in all three cell lines, by >70% in at least one cell line, and with an EC50 value Pacritinib reduces glucose consumption in all three SqCLC cell lines with an EC50 value of 1.2 µM in cell culture and blocks glucose consumption in cell line xenografts in vivo without affecting glucose consumption in healthy tissues. In the SqCLC cell lines, Pacritinib decreases protein levels of Hexokinase 1 and Hexokinase 2 as well as hexokinase activity as measured by a FRET-based glucose sensor. Hexokinase 1 overexpression in the SqCLC cell lines blocks Pacritinib from inhibiting glucose consumption. Pacritinib targets JAK2, TYK2, FLT3, and additional kinases at low nanomolar concentrations in vitro. Additional small molecule inhibitors of JAK2 and TYK2 had no effect on SqCLC glucose consumption. However additional inhibitors of FLT3 blocked glucose consumption in all three SqCLC cell lines. FLT3 overexpression increased SqCLC glucose consumption and blocked Pacritinib from inhibiting glucose consumption. In conclusion, using our high-throughput technology, we discovered that FLT3 is a selective and targetable driver of glucose consumption in SqCLC. Our data suggest that FLT3 activates glucose consumption by increasing Hexokinase 1 levels. Citation Format: Chiara Ghezzi, Robert Damoiseaux, Peter M. Clark. FLT3 is a major driver of glucose consumption in squamous cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 91.","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75001433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2165: Reproducibility of a 12-gene panel and development of user-friendly nomogram-based calculator for clinical management of surgically resected non-small cell lung cancer patients","authors":"L. F. Leal, M. S. Gonçalves, Luciane Sussuchi da Silva, M. A. Lima, M.B.P.P. Olveira, Shen Yin, H. N. Bastos, P. Marchi, Josiane M Dias, F. Carneiro, C. Moura, Vinicius Duval Silva, Ignacio I. Witsuba, Xie Yang, R. Reis","doi":"10.1158/1538-7445.AM2021-2165","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2165","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"76 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75140734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2360: Identifying differentially expressed miRNAs in CRC stem cell subpopulations","authors":"Victoria A. Stark, Vignesh Viswanathan, C. Facey, Lynn M. Opdenaker, B. Boman","doi":"10.1158/1538-7445.AM2021-2360","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2360","url":null,"abstract":"Our research goal is to discover the molecular mechanisms behind tumor heterogeneity in CRC. We previously showed that CRCs contain multiple subpopulations of cancer stem cells (CSCs) which may explain the occurrence tumor heterogeneity and resistance to treatment. To determine how CSC sub-populations might arise, we are studying miRNA expression in CRC SCs. MicroRNAs are known to regulate SC phenotype and are found to be dysregulated in many cancers. Hypothesis: Tumor heterogeneity results from existence of multiple CSC subpopulations that are regulated by distinct miRNAs. Accordingly, we are using bioinformatics and miRNA profiling to identify miRNAs that target SC genes in CRCs. Indeed, our miRNA expression profiling of normal and malignant ALDH+ human colonic SCs showed that miRNA92a targets the SC gene LRIG1 and upregulation of miRNA92a leads to decreased LRIG1 expression. We also discovered that miRNA23b targets the SC gene LGR5 and miRNA23b is upregulated in ALDH+ CSCs. We have identified several other candidate miRNAs that are predicted to target CD166, ALDH1A1, BMI1, LRG5, and LRIG1 SC genes. We are currently in the process of validating whether these miRNAs contribute to emergence of specific CSC sub-populations in CRCs. Thus, identifying miRNAs that regulate CSC subpopulations should provide new strategies to modulate CSC composition in order to sensitize tumors to treatments. Citation Format: Victoria A. Stark, Vignesh Viswanathan, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. Identifying differentially expressed miRNAs in CRC stem cell subpopulations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2360.","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77670990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}