Metastatic niche mediated activation of metastasis initiating cells in ovarian cancer through miR-193b-3p downregulation via the ERK/EZH2/DNMT1 axis

Abstract

Extensive metastasis at the time of diagnosis is a major contributor to the poor prognosis of ovarian cancer (OC) patients. There is a critical need to better understand the mechanism of regulation of metastasis to develop effective treatment strategies targeting the process. Metastasis initiating cells (MICs) have cancer stem cell-like properties along with the ability to invade. Their potential role in OC is unique as the dissemination from the primary tumors involves passive processes like exfoliation. However, the role of MICs during OC metastatic colonization is critical and poorly understood. Using an organotypic 3D culture model of the human omentum, we have studied the productive crosstalk between OC MICs and the metastatic microenvironment. We report the role of miR-193b-3p, a clinically relevant metastasis suppressor microRNA, which is downregulated in the OC by paracrine signals from the microenvironment, inducing the MIC phenotype. Using heterotypic coculture models, conditioned medium experiments, secretome analysis, inhibition, and rescue experiments, we show that bFGF and IGFBP6 secreted by mesothelial cells in the microenvironment induce miR-193b-3p downregulation in OC MICs via the ERK/EZH2/DNMT1 axis. The miR-193b-3p downregulation induced an increased expression of its target cyclin D1, which imparted a cancer stem cell phenotype. Urokinase, another target of miR-193b-3p, induced invasive growth. Together, these targets impart the MIC phenotype to the OC cells. miR-193b-3p replacement therapy could suppress metastasis in a patient derived xenograft model of OC metastasis, indicating the translational potential of this approach to target MICs in OC patients.