ATAC-sequencing on mesenchymal stem cells

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.