Extracellular vesicles derived from EZH2-high ovarian cancer cells facilitate omental metastasis by inducing Periostin+ fibroblasts.

The frequent omental metastasis of ovarian cancer (OvCa) at initial diagnosis is due to the omental premetastatic microenvironment, which is rich in activated fibroblasts. However, the molecular events driving the phenotypic transformation of omental fibroblasts that favor metastasis remain largely unexplored. Previously, we found that tumoral enhancer of zest homolog 2 (EZH2), a key epigenetic regulator catalyzing trimethylation at H3K27, played a crucial role in OvCa metastasis. In this study, we revealed that extracellular vesicles (EVs) derived from EZH2-high OvCa cells induce the expression of Periostin (POSTN), but not α-SMA, in omental fibroblasts, facilitating tumor metastasis. Nude mice with intraperitoneal injection of EVs before tumor cell inoculation showed that EVs derived from EZH2-high ovarian cancer cells promote omental metastasis. Human primary omental fibroblasts cocultured with EVs, especially those derived from EZH2-high OvCa cells, exhibited boosted migration, invasion capacities and conditioned medium from EV-activated fibroblasts promotes cancer cell migration, invasion and proliferation. These results may provide novel insight into EZH2-targeted therapy for ovarian carcinoma with intraperitoneal dissemination.