Molecular Cancer Research最新文献_第3页

Stress and Obesity Signaling Converge on CREB Phosphorylation to Promote Pancreatic Cancer. 应激和肥胖信号汇聚在CREB磷酸化上促进胰腺癌。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0785

Xiaoying Sun, Yaroslav Teper, James Sinnett-Smith, Mineh Markarian, O Joe Hines, Gang Li, Guido Eibl, Enrique Rozengurt

{"title":"Stress and Obesity Signaling Converge on CREB Phosphorylation to Promote Pancreatic Cancer.","authors":"Xiaoying Sun, Yaroslav Teper, James Sinnett-Smith, Mineh Markarian, O Joe Hines, Gang Li, Guido Eibl, Enrique Rozengurt","doi":"10.1158/1541-7786.MCR-24-0785","DOIUrl":"10.1158/1541-7786.MCR-24-0785","url":null,"abstract":"One of the deadliest types of cancer is pancreatic ductal adenocarcinoma (PDAC). Chronic stress and obesity are recognized as risk factors for PDAC. We hypothesized that the combination of stress and obesity strongly promotes pancreatic cancer development and growth. Here, we show that the stress mediator norepinephrine and the β-adrenergic receptor agonist isoproterenol rapidly stimulate cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation at Ser133 in human PDAC cells. Exposure to the nonselective β-adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551, blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. Stimulation of PDAC cells with neurotensin, a neuropeptide implicated in obesity and PDAC, also stimulated CREB phosphorylation at Ser133. Mechanistically, norepinephrine induced CREB phosphorylation at Ser133 via PKA, whereas neurotensin promoted CREB phosphorylation predominantly through protein kinase D. Our results indicate that CREB is a point of signal convergence that mediates proliferation in PDAC cells and raised the possibility that stress and diet cooperate in promoting PDAC in vivo. To test this notion, mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, calorie diet that promotes early PDAC development were subjected to social isolation stress. We show that social isolation stress induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia) in KC mice subjected to an obesogenic high fat, calorie diet. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"236-249"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gut Microbiota-Mediated hsa_circ_0126925 Targets BCAA Metabolic Enzyme BCAT2 to Exacerbate Colorectal Cancer Progression. 肠道菌群介导的hsa_circ_0126925靶向BCAA代谢酶BCAT2，加速结直肠癌进展。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0434

Huihui Yao, Jiancheng Xu, Aina Zhou, Danyang Shen, Qiuchen Dong, Xiaodong Yang, Mengyu Li, Xiuwei Mi, Yang Lu, Runze Zhong, Xinyu Shi, Qingliang Tai, Guoliang Chen, Bo Shi, Liang Sun, Diyuan Zhou, Yizhou Yao, Songbing He

{"title":"Gut Microbiota-Mediated hsa_circ_0126925 Targets BCAA Metabolic Enzyme BCAT2 to Exacerbate Colorectal Cancer Progression.","authors":"Huihui Yao, Jiancheng Xu, Aina Zhou, Danyang Shen, Qiuchen Dong, Xiaodong Yang, Mengyu Li, Xiuwei Mi, Yang Lu, Runze Zhong, Xinyu Shi, Qingliang Tai, Guoliang Chen, Bo Shi, Liang Sun, Diyuan Zhou, Yizhou Yao, Songbing He","doi":"10.1158/1541-7786.MCR-24-0434","DOIUrl":"10.1158/1541-7786.MCR-24-0434","url":null,"abstract":"Recent evidence indicates that a high-fat diet can promote tumor development, especially colorectal cancer, by influencing the microbiota. Regulatory circular RNA (circRNA) plays an important role in modulating host-microbe interactions; however, the specific mechanisms by which circRNAs influence cancer progression by regulating these interactions remain unclear. Here, we report that consumption of a high-fat diet modulates the microbiota by specifically upregulating the expression of the noncoding RNA hsa_circ_0126925 (herein, referred to as circ_0126925) in colorectal cancer. Acting as a scaffold, circ_0126925 hinders the recruitment of the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) to branched-chain amino acid transaminase 2 (BCAT2), leading to reduced degradation of BCAT2. This reduction in targeted degradation of BCAT2 can protect tumors from limited branched-chain amino acid (BCAA) interference by improving the metabolism of BCAAs in colorectal cancer. Taken together, these data demonstrate that circ_0126925 plays a critical role in promoting the progression of colorectal cancer by maintaining BCAA metabolism and provide insight into the functions and crosstalk of circ_0126925 in host-microbe interactions in colorectal cancer. Implications: This study preliminarily confirms that circRNAs do indeed respond to microbiota/microbial metabolites, providing further evidence for the potential development of circRNAs as diagnostic tools and/or therapeutic agents to alleviate microbiome-related pathology in humans.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"202-218"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cells in the Polyaneuploid Cancer Cell State Are Prometastatic. 多非整倍体癌细胞状态的细胞是前转移的。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0689

Mikaela M Mallin, Louis T A Rolle, Michael J Schmidt, Shilpa Priyadarsini Nair, Amado J Zurita, Peter Kuhn, James Hicks, Kenneth J Pienta, Sarah R Amend

{"title":"Cells in the Polyaneuploid Cancer Cell State Are Prometastatic.","authors":"Mikaela M Mallin, Louis T A Rolle, Michael J Schmidt, Shilpa Priyadarsini Nair, Amado J Zurita, Peter Kuhn, James Hicks, Kenneth J Pienta, Sarah R Amend","doi":"10.1158/1541-7786.MCR-24-0689","DOIUrl":"10.1158/1541-7786.MCR-24-0689","url":null,"abstract":"Our research aims to understand the adaptive-ergo potentially metastatic-responses of prostate cancer to changing microenvironments. Emerging evidence implicates a role of the polyaneuploid cancer cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency. Mounting in vitro evidence supports increased metastatic potential of cells in the PACC state. Additionally, our recent retrospective study revealed that PACC presence in patient prostate tumors at the time of radical prostatectomy was predictive of future metastasis. To test for a causative relationship between PACC state biology and metastasis in prostate cancer, we leveraged a novel method designed for flow cytometric detection of circulating tumor cells (CTC) and disseminated tumor cells (DTC) from animal models. This approach provides both quantitative and qualitative information about the number and PACC status of recovered CTCs and DTCs. Specifically, we applied this approach to the analysis of subcutaneous, caudal artery, and intracardiac murine models. Collating data from all models, we found that 74% of recovered CTCs and DTCs were in the PACC state. Furthermore, in vivo colonization assays proved that PACC populations can regain proliferative capacity at metastatic sites. Additional in vitro analyses revealed a PACC-specific partial epithelial-to-mesenchymal transition phenotype and a prometastatic secretory profile, together providing preliminary evidence of prometastatic mechanisms specific to the PACC state. Implications: Considering that many anticancer agents induce the PACC state, our data position the increased metastatic competency of PACC state cells as an important unforeseen ramification of neoadjuvant regimens, which may help explain clinical correlations between chemotherapy and metastatic progression.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"219-235"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cross-talk between WNT Signaling and Ferroptosis in Cancer. 癌症中WNT信号与铁下垂之间的串扰。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0880

Zheng Wang, Zhixiang Zhang, Yunhui Yue, Yifan Hou, Yujia Cao, Changsheng Guo, Xiaobo Nie, Junqing Hou

{"title":"Cross-talk between WNT Signaling and Ferroptosis in Cancer.","authors":"Zheng Wang, Zhixiang Zhang, Yunhui Yue, Yifan Hou, Yujia Cao, Changsheng Guo, Xiaobo Nie, Junqing Hou","doi":"10.1158/1541-7786.MCR-24-0880","DOIUrl":"10.1158/1541-7786.MCR-24-0880","url":null,"abstract":"Cancer remains one of the most formidable challenges in the medical field in this century, largely because of its poorly understood pathogenesis. Fortunately, recent advancements in the understanding of cancer pathogenesis have helped identify more therapeutic targets for improved treatment outcomes. The WNT signaling pathways are highly conserved cascades that participate in diverse physiologic processes, such as embryonic development, tissue homeostasis, and tissue regeneration. Ferroptosis, a unique iron-dependent form of cell death that is distinct from apoptosis, is driven by lipid peroxidation and excessive reactive oxygen species production. Emerging evidence shows that the dysregulation of WNT signaling pathways and ferroptosis, as well as their intricate cross-talk, plays crucial roles in cancer progression and therapeutic resistance, indicating their potential as targets for cancer therapies. This review provides a comprehensive overview of the current understanding of the cross-talk between WNT signaling pathways and ferroptosis in the pathogenesis and progression of cancer, with a specific focus on the regulatory role of the canonical WNT cascade in cancer-related ferroptosis. In addition, we discuss the pharmacologic mechanisms of current strategies that inhibit canonical WNT signaling and/or induce ferroptosis in cancer treatment. We propose that combining canonical WNT pathway inhibitors and ferroptosis inducers with current therapies represents a promising therapeutic strategy for personalized cancer treatment.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"175-189"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tumor-Derived EBV-miR-BART2-5p Promotes Nasopharyngeal Carcinoma Metastasis by Inducing Premetastatic Endothelial Cell Pyroptosis. 肿瘤衍生的EBV-miR-BART2-5p通过诱导转移前内皮细胞热解促进鼻咽癌转移。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0165

Xingrui Chen, Qiqi Li, Xiaoyan Fu, Jike Li, Jun Deng, Qianbing Zhang, Mengying Qiu, Xiaoming Lyu, Linbo Cai, Hainan Li, Xin Li, Kaitai Yao, Jiahong Wang, Zhongxi Huang, Liang Chen, Jiangyu Zhang, Dengke Li

{"title":"Tumor-Derived EBV-miR-BART2-5p Promotes Nasopharyngeal Carcinoma Metastasis by Inducing Premetastatic Endothelial Cell Pyroptosis.","authors":"Xingrui Chen, Qiqi Li, Xiaoyan Fu, Jike Li, Jun Deng, Qianbing Zhang, Mengying Qiu, Xiaoming Lyu, Linbo Cai, Hainan Li, Xin Li, Kaitai Yao, Jiahong Wang, Zhongxi Huang, Liang Chen, Jiangyu Zhang, Dengke Li","doi":"10.1158/1541-7786.MCR-24-0165","DOIUrl":"10.1158/1541-7786.MCR-24-0165","url":null,"abstract":"Extravasation is a key step in tumor metastasis. Epstein‒Barr virus plays a crucial role in nasopharyngeal carcinoma (NPC) metastasis. However, the functions and molecular mechanisms of Epstein‒Barr virus during tumor cell extravasation remain unclear. Here, we showed that the expression of pyroptosis-associated proteins is greater in the endothelial cells of metastatic NPC tissues than in those of nontumor tissues exosomes derived from NPC cells promoted endothelial cell pyroptosis, vascular permeability, and tumor cell extravasation. Moreover, we found that BART2-5p is abundant in serum exosomes from patients with NPC metastasis and in NPC cells and that it regulates endothelial cell pyroptosis in premetastatic organs via MRE11A. Exosomes containing a BART2-5p inhibitor and AAV-MRE11A attenuated endothelial cell pyroptosis and tumor metastasis. Moreover, in the endothelial cells of metastatic tissues from patients with NPC, the BART2-5p level was positively associated with pyroptosis-related protein expression. Collectively, our findings suggest that exosomal BART2-5p is involved in premetastatic niche formation, identifying secreted BART2-5p as a potential therapeutic target for NPC metastasis. Implications: The finding that secreted BART2-5p is involved in premetastatic niche formation may aid the development of a potential therapeutic target for NPC metastasis.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"250-262"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SMURF2 facilitates GAP17 Isoform 1 membrane displacement to promote mutant p53-KRAS oncogenic synergy.

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-02-20 DOI: 10.1158/1541-7786.MCR-24-0701

Paramita Ray, Shirish Shukla, Yaqing Zhang, Katelyn L Donahue, Derek J Nancarrow, Srimathi Kasturirangan, Sunita Shankar, Kyle Cuneo, Dafydd Thomas, Shirish M Gadgeel, Theodore S Lawrence, Marina Pasca di Magliano, Dipankar Ray

{"title":"SMURF2 facilitates GAP17 Isoform 1 membrane displacement to promote mutant p53-KRAS oncogenic synergy.","authors":"Paramita Ray, Shirish Shukla, Yaqing Zhang, Katelyn L Donahue, Derek J Nancarrow, Srimathi Kasturirangan, Sunita Shankar, Kyle Cuneo, Dafydd Thomas, Shirish M Gadgeel, Theodore S Lawrence, Marina Pasca di Magliano, Dipankar Ray","doi":"10.1158/1541-7786.MCR-24-0701","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0701","url":null,"abstract":"Cooperativity between mutant p53 and mutant KRAS, although recognized, is poorly understood. In pancreatic cancer, mutant p53 induces splicing factor hnRNPK causing isoform switch producing overexpression of GTPase activating protein 17 isoform 1 (GAP17-1). GAP17-1 is mis-localized in the cytosol, instead of the membrane, due to insertion of exon 17 encoding a PPLP motif, thus allowing mutant KRAS to remain in the GTP bound hyperactive state. However, the role of PPLP in influencing GAP17-1 mis-localization remains unclear. We show that Smad Ubiquitination Regulatory Factor 2 (SMURF2), a known stabilizer of mutant KRAS, interacts with GAP17-1 via the PPLP motif and displaces it from the membrane, facilitating mutant p53 mediated mutant KRAS hyperactivation. We used cell lines with known KRAS and TP53 mutations, characterized Smurf2 expression in multiple pancreatic cancer mouse models (iKras*; iKras*, p53*, and p48-Cre; Kras*) and performed single cell RNAseq and tissue microarray on preclinical and clinical samples. We found that SMURF2 silencing profoundly reduces survival of mutant TP53; KRAS driven cells. We show that a GAP17-1 AALA mutant does not bind to SMURF2, stays in the membrane, and keeps mutant KRAS in the GDP bound state to inhibit downstream signaling. In mouse models, mutant KRAS and SMURF2 upregulation are correlated in pancreatic intraepithelial neoplasia (PanIN) and ductal adenocarcinoma (PDA) lesions. Furthermore, PDA patients who received neoadjuvant therapy and express moderate to high SMURF2 show decreased overall survival (p=0.04). Implications: In TP53 and KRAS double mutated pancreatic cancer, SMURF2 driven GAP17-1 membrane expulsion facilitates mutant p53-KRAS oncogenic synergy.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extrachromosomal DNA dynamics contribute to intratumoural receptor tyrosine kinase genetic heterogeneity and drug resistance in gastric cancer.

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-02-19 DOI: 10.1158/1541-7786.MCR-24-0741

Kazuki Kanayama, Hiroshi Imai, Ryotaro Hashizume, Chise Matsuda, Eri Usugi, Yoshifumi S Hirokawa, Masatoshi Watanabe

{"title":"Extrachromosomal DNA dynamics contribute to intratumoural receptor tyrosine kinase genetic heterogeneity and drug resistance in gastric cancer.","authors":"Kazuki Kanayama, Hiroshi Imai, Ryotaro Hashizume, Chise Matsuda, Eri Usugi, Yoshifumi S Hirokawa, Masatoshi Watanabe","doi":"10.1158/1541-7786.MCR-24-0741","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0741","url":null,"abstract":"Chromosomal instability in gastric cancer cells is associated with the amplification of oncogenes that encode receptor tyrosine kinases (RTKs), such as HER2 and FGFR2; such gene amplification varies from cell to cell and manifests as genetic heterogeneity within tumours. The intratumoural genetic heterogeneity of RTK gene amplification causes heterogeneity in RTK protein expression, which has been suggested to be associated with therapeutic resistance to RTK inhibitors; however, the underlying mechanism is not fully understood. Here, we show that extrachromosomal DNA (ecDNA) causes intratumoural genetic heterogeneity in RTKs and drug resistance due to diverse dynamic changes. We analysed the dynamics of FGFR2 and MYC ecDNA in a gastric cancer cell line after single-cell cloning. Similar to those in parental cells, the copy numbers of FGFR2 and MYC in subclones differed significantly between cells, indicating intraclonal genetic heterogeneity. Furthermore, the ecDNA composition differed between subclones, which affected FGFR2 protein expression and drug sensitivity. Interestingly, clone cells that were resistant to the FGFR2 inhibitor AZD4547 presented diverse changes in ecDNA, including chimeric ecDNA, large ecDNA and increased ecDNA numbers; these changes were associated with high expression and rephosphorylation of FGFR2. Conversely, when resistant clone cells were cultured under conditions that excluded AZD4547, the ecDNA status became similar to that of the original clone cells, and the inhibitory effect on cell growth was restored. Implications: Our results show that dynamic quantitative and qualitative changes in ecDNA can drive the intratumoural genetic heterogeneity of RTKs and resistance to RTK inhibitors.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SIRT2 regulates the SMARCB1 loss-driven differentiation block in ATRT.

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-02-17 DOI: 10.1158/1541-7786.MCR-24-0926

Irina Alimova, Dong Wang, John DeSisto, Etienne Danis, Senthilnath Lakshmanachetty, Eric Prince, Gillian Murdock, Angela Pierce, Andrew Donson, Ilango Balakrishnan, Natalie Serkova, Hening Lin, Nicholas K Foreman, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar

{"title":"SIRT2 regulates the SMARCB1 loss-driven differentiation block in ATRT.","authors":"Irina Alimova, Dong Wang, John DeSisto, Etienne Danis, Senthilnath Lakshmanachetty, Eric Prince, Gillian Murdock, Angela Pierce, Andrew Donson, Ilango Balakrishnan, Natalie Serkova, Hening Lin, Nicholas K Foreman, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar","doi":"10.1158/1541-7786.MCR-24-0926","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0926","url":null,"abstract":"Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive pediatric brain tumor driven by the loss of SMARCB1, which results in epigenetic dysregulation of the genome. SMARCB1 loss affects lineage commitment and differentiation by controlling gene expression. We hypothesized that additional epigenetic factors co-operate with SMARCB1 loss to control cell self-renewal and drive ATRT. We performed an unbiased epigenome targeted screen to identify genes that co-operate with SMARCB1 and identified SIRT2 as a key regulator. Using in vitro pluripotency assays combined with in vivo single cell RNA transcriptomics, we examined the impact of SIRT2 on differentiation of ATRT cells. We employed a series of orthotopic murine models treated with SIRT2 inhibitors to examine the impact on survival and clinical applicability. We found that ATRT cells are highly dependent on SIRT2 for survival. Genetic or chemical inhibition led to decrease cell self-renewal and induction of differentiation in tumor spheres and in vivo models. We found that SIRT2 inhibition can restore gene expression programs lost due to SMARCB1 loss and reverse the differentiation block in ATRT in vivo. Finally, we showed the in vivo efficacy of a clinically relevant inhibitor demonstrating SIRT2 inhibition as a potential therapeutic strategy. We concluded that SIRT2 is a critical dependency in SMARCB1 deficient ATRT cells and acts by controlling the pluripotency-differentiation switch. Thus, SIRT2 inhibition is a promising therapeutic approach that warrants further investigation and clinical development. Implications: SIRT2 inhibition is a molecular vulnerability in SMARCB1-deleted tumors.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epigenetic dysregulation of retrotransposons in cancer.

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-02-13 DOI: 10.1158/1541-7786.MCR-24-0744

Danny Leung, Kwok Yu Liu

引用次数: 0

KSR1 mediates small-cell lung carcinoma tumor initiation and cisplatin resistance.

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-02-10 DOI: 10.1158/1541-7786.MCR-24-0652

Deepan Chatterjee, Robert A Svoboda, Dianna H Huisman, Benjamin J Drapkin, Heidi M Vieira, Chaitra Rao, James W Askew, Kurt W Fisher, Robert E Lewis

{"title":"KSR1 mediates small-cell lung carcinoma tumor initiation and cisplatin resistance.","authors":"Deepan Chatterjee, Robert A Svoboda, Dianna H Huisman, Benjamin J Drapkin, Heidi M Vieira, Chaitra Rao, James W Askew, Kurt W Fisher, Robert E Lewis","doi":"10.1158/1541-7786.MCR-24-0652","DOIUrl":"10.1158/1541-7786.MCR-24-0652","url":null,"abstract":"Small-cell lung cancer (SCLC) has a dismal five-year survival rate of less than 7%, with limited advances in first line treatment over the past four decades. Tumor-initiating cells (TICs) contribute to resistance and relapse, a major impediment to SCLC treatment. Here, we identify Kinase Suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK signaling cascade, as a critical regulator of SCLC TIC formation and tumor initiation in vivo. We further show that KSR1 mediates cisplatin resistance in SCLC. While 50-70% of control cells show resistance after 6-week exposure to cisplatin, CRISPR/Cas9-mediated KSR1 knockout prevents resistance in >90% of SCLC cells in ASCL1, NeuroD1, and POU2F3 subtypes. KSR1 KO significantly enhances the ability of cisplatin to decrease SCLC TICs via in vitro extreme limiting dilution analysis (ELDA), indicating that KSR1 disruption enhances the cisplatin toxicity of cells responsible for therapeutic resistance and tumor initiation. The ability of KSR1 disruption to prevent cisplatin resistant in H82 tumor xenograft formation supports this conclusion. Previous studies indicate ERK activation inhibits SCLC tumor growth and development. We observe a minimal effect of pharmacological ERK inhibition on cisplatin resistance and no impact on TIC formation via in vitro ELDA. However, mutational analysis of the KSR1 DEF domain, which mediates interaction with ERK, suggests that ERK interaction with KSR1 is essential for KSR1-driven cisplatin resistance. These findings reveal KSR1 as a potential therapeutic target across multiple SCLC subtypes. Implications: Genetic manipulation of KSR1 in SCLC reveals its contribution to cisplatin resistance and tumor initiation.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0