Epigenomic Reprogramming toward Mesenchymal-Epithelial Transition in Ovarian-Cancer-Associated Mesenchymal Stem Cells Drives Metastasis

Cell Rep. 2020 Dec 8;33(10):108473. doi: 10.1016/j.celrep.2020.108473.


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.

Keywords: EZH2; WT1; carcinoma-associated mesenchymal stem cells; epigenomic reprogramming; mesenchymal-to-epithelial transition; metastasis; ovarian cancer; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinoma, Ovarian Epithelial / genetics
  • Carcinoma, Ovarian Epithelial / metabolism
  • Carcinoma, Ovarian Epithelial / pathology
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Epigenome / genetics
  • Epigenomics / methods
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Gene Expression / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Mesenchymal Stem Cells / physiology
  • Mice
  • Mice, Inbred NOD
  • Neoplasm Metastasis / genetics*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Primary Cell Culture
  • Signal Transduction / genetics
  • WT1 Proteins / genetics
  • WT1 Proteins / metabolism


  • WT1 Proteins
  • WT1 protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein