Zhao Lin, Megan E Roche, Víctor Díaz-Barros, Marina Domingo-Vidal, Diana Whitaker-Menezes, Madalina Tuluc, Guldeep Uppal, Jaime Caro, Joseph M Curry, Ubaldo Martinez-Outschoorn
{"title":"MiR-200c 可重塑成纤维细胞,使其重现乳腺癌进展过程中 CAF 的表型。","authors":"Zhao Lin, Megan E Roche, Víctor Díaz-Barros, Marina Domingo-Vidal, Diana Whitaker-Menezes, Madalina Tuluc, Guldeep Uppal, Jaime Caro, Joseph M Curry, Ubaldo Martinez-Outschoorn","doi":"10.15698/cst2024.03.293","DOIUrl":null,"url":null,"abstract":"<p><p>Mesenchymal-epithelial plasticity driving cancer progression in cancer-associated fibroblasts (CAFs) is undetermined. This work identifies a subgroup of CAFs in human breast cancer exhibiting mesenchymal-to-epithelial transition (MET) or epithelial-like profile with high miR-200c expression. MiR-200c overexpression in fibroblasts is sufficient to drive breast cancer aggressiveness. Oxidative stress in the tumor microenvironment induces miR-200c by DNA demethylation. Proteomics, RNA-seq and functional analyses reveal that miR-200c is a novel positive regulator of NFκB-HIF signaling via COMMD1 downregulation and stimulates pro-tumorigenic inflammation and glycolysis. Reprogramming fibroblasts toward MET via miR-200c reduces stemness and induces a senescent phenotype. This pro-tumorigenic profile in CAFs fosters carcinoma cell resistance to apoptosis, proliferation and immunosuppression, leading to primary tumor growth, metastases, and resistance to immuno-chemotherapy. Conversely, miR-200c inhibition in fibroblasts restrains tumor growth with abated oxidative stress and an anti-tumorigenic immune environment. This work determines the mechanisms by which MET in CAFs via miR-200c transcriptional enrichment with DNA demethylation triggered by oxidative stress promotes cancer progression. CAFs undergoing MET trans-differentiation and senescence coordinate heterotypic signaling that may be targeted as an anti-cancer strategy.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10927306/pdf/","citationCount":"0","resultStr":"{\"title\":\"MiR-200c reprograms fibroblasts to recapitulate the phenotype of CAFs in breast cancer progression.\",\"authors\":\"Zhao Lin, Megan E Roche, Víctor Díaz-Barros, Marina Domingo-Vidal, Diana Whitaker-Menezes, Madalina Tuluc, Guldeep Uppal, Jaime Caro, Joseph M Curry, Ubaldo Martinez-Outschoorn\",\"doi\":\"10.15698/cst2024.03.293\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Mesenchymal-epithelial plasticity driving cancer progression in cancer-associated fibroblasts (CAFs) is undetermined. This work identifies a subgroup of CAFs in human breast cancer exhibiting mesenchymal-to-epithelial transition (MET) or epithelial-like profile with high miR-200c expression. MiR-200c overexpression in fibroblasts is sufficient to drive breast cancer aggressiveness. Oxidative stress in the tumor microenvironment induces miR-200c by DNA demethylation. Proteomics, RNA-seq and functional analyses reveal that miR-200c is a novel positive regulator of NFκB-HIF signaling via COMMD1 downregulation and stimulates pro-tumorigenic inflammation and glycolysis. Reprogramming fibroblasts toward MET via miR-200c reduces stemness and induces a senescent phenotype. This pro-tumorigenic profile in CAFs fosters carcinoma cell resistance to apoptosis, proliferation and immunosuppression, leading to primary tumor growth, metastases, and resistance to immuno-chemotherapy. Conversely, miR-200c inhibition in fibroblasts restrains tumor growth with abated oxidative stress and an anti-tumorigenic immune environment. This work determines the mechanisms by which MET in CAFs via miR-200c transcriptional enrichment with DNA demethylation triggered by oxidative stress promotes cancer progression. CAFs undergoing MET trans-differentiation and senescence coordinate heterotypic signaling that may be targeted as an anti-cancer strategy.</p>\",\"PeriodicalId\":36371,\"journal\":{\"name\":\"Cell Stress\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-03-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10927306/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Stress\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.15698/cst2024.03.293\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Stress","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.15698/cst2024.03.293","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
癌症相关成纤维细胞(CAFs)的间充质-上皮可塑性是癌症进展的驱动因素,这一点尚未确定。这项研究确定了人类乳腺癌中的一个CAFs亚群,该亚群表现出间质向上皮转化(MET)或上皮样特征,具有高miR-200c表达。成纤维细胞中MiR-200c的过表达足以驱动乳腺癌的侵袭性。肿瘤微环境中的氧化应激通过 DNA 去甲基化诱导 miR-200c。蛋白质组学、RNA-seq和功能分析表明,miR-200c是通过COMMD1下调NFκB-HIF信号的新型正调控因子,并刺激促肿瘤炎症和糖酵解。通过 miR-200c 使成纤维细胞向 MET 方向重编程可降低干性并诱导衰老表型。CAFs中的这种促致瘤性特征会促进癌细胞对凋亡、增殖和免疫抑制的抵抗,从而导致原发性肿瘤生长、转移和对免疫化疗的抵抗。相反,抑制成纤维细胞中的 miR-200c 则可抑制肿瘤生长,减轻氧化应激和抗肿瘤免疫环境。这项研究确定了MET在CAFs中通过miR-200c转录富集和氧化应激引发的DNA去甲基化促进癌症进展的机制。经历 MET 跨分化和衰老的 CAFs 可协调异型信号转导,从而成为抗癌策略的目标。
MiR-200c reprograms fibroblasts to recapitulate the phenotype of CAFs in breast cancer progression.
Mesenchymal-epithelial plasticity driving cancer progression in cancer-associated fibroblasts (CAFs) is undetermined. This work identifies a subgroup of CAFs in human breast cancer exhibiting mesenchymal-to-epithelial transition (MET) or epithelial-like profile with high miR-200c expression. MiR-200c overexpression in fibroblasts is sufficient to drive breast cancer aggressiveness. Oxidative stress in the tumor microenvironment induces miR-200c by DNA demethylation. Proteomics, RNA-seq and functional analyses reveal that miR-200c is a novel positive regulator of NFκB-HIF signaling via COMMD1 downregulation and stimulates pro-tumorigenic inflammation and glycolysis. Reprogramming fibroblasts toward MET via miR-200c reduces stemness and induces a senescent phenotype. This pro-tumorigenic profile in CAFs fosters carcinoma cell resistance to apoptosis, proliferation and immunosuppression, leading to primary tumor growth, metastases, and resistance to immuno-chemotherapy. Conversely, miR-200c inhibition in fibroblasts restrains tumor growth with abated oxidative stress and an anti-tumorigenic immune environment. This work determines the mechanisms by which MET in CAFs via miR-200c transcriptional enrichment with DNA demethylation triggered by oxidative stress promotes cancer progression. CAFs undergoing MET trans-differentiation and senescence coordinate heterotypic signaling that may be targeted as an anti-cancer strategy.
Cell StressBiochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍:
Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging.
The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.