Epigenomic Reprogramming toward Mesenchymal-Epithelial Transition in Ovarian-Cancer-Associated Mesenchymal Stem Cells Drives Metastasis.
A role for cancer cell epithelial-to-mesenchymal transition (EMT) in cancer is well established. Here, we show that, in addition to cancer cell EMT, ovarian cancer cell metastasis relies on an epigenomic mesenchymal-to-epithelial transition (MET) in host mesenchymal stem cells (MSCs). These reprogrammed MSCs, termed carcinoma-associated MSCs (CA-MSCs), acquire pro-tumorigenic functions and directly bind cancer cells to serve as a metastatic driver/chaperone. Cancer cells induce this epigenomic MET characterized by enhancer-enriched DNA hypermethylation, altered chromatin accessibility, and differential histone modifications. This phenomenon appears clinically relevant, as CA-MSC MET is highly correlated with patient survival. Mechanistically, mirroring MET observed in development, MET in CA-MSCs is mediated by WT1 and EZH2. Importantly, EZH2 inhibitors, which are clinically available, significantly inhibited CA-MSC-mediated metastasis in mouse models of ovarian cancer.
['Fan|Huihui|H|', 'Atiya|Huda I|HI|', 'Wang|Yeh|Y|', 'Pisanic|Thomas R|TR|', 'Wang|Tza-Huei|TH|', 'Shih|Ie-Ming|IM|', 'Foy|Kelly K|KK|', 'Frisbie|Leonard|L|', 'Buckanovich|Ronald J|RJ|', 'Chomiak|Alison A|AA|', 'Tiedemann|Rochelle L|RL|', 'Rothbart|Scott B|SB|', 'Chandler|Chelsea|C|', 'Shen|Hui|H|', 'Coffman|Lan G|LG|']
D000818:Animals D000077216:Carcinoma, Ovarian Epithelial D002454:Cell Differentiation D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D000071221:Enhancer of Zeste Homolog 2 Protein D000081122:Epigenome D057890:Epigenomics D058750:Epithelial-Mesenchymal Transition D005260:Female D015870:Gene Expression D015972:Gene Expression Regulation, Neoplastic D006801:Humans D059630:Mesenchymal Stem Cells D051379:Mice D016688:Mice, Inbred NOD D009362:Neoplasm Metastasis D010051:Ovarian Neoplasms D061251:Primary Cell Culture D015398:Signal Transduction D025721:WT1 Proteins
epigenomic reprogramming metastasis ovarian cancer mesenchymal-to-epithelial transition WT1 EZH2 carcinoma-associated mesenchymal stem cells tumor microenvironment