Journal
CELL REPORTS
Volume 33, Issue 10, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108473
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Funding
- NIH/NCI [7K08CA211362-02, 1R37CA230748]
- Tina's Wish Rising Star
- Mary Kay Foundation Cancer Research grant
- DoD Ovarian Cancer, Omics Consortium Development Award
- Ovarian Cancer Research Alliance's Liz Tilberis award [373933]
- NIH [R35GM124736, F32CA225043]
- American Cancer Society-Michigan Cancer Research Fund [PF-16-245-01-DMC]
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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-toepithelial 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.
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