Generation of Stable Epithelial–Mesenchymal Hybrid Cancer Cells with Tumorigenic Potential

SIMPLE SUMMARY: Cancer spreading into different organs, or cancer metastasis, remains the major clinical problem in almost all cancer types. Cancer metastasis is known to be governed by cancer cell adaptation and differentiation in the process known as epithelial-to-mesenchymal transition (EMT). Recently, this process has been shown to yield to epithelial and mesenchymal like properties, resulting in what is known as epithelial/mesenchymal (E/M) hybrid cancer cells. However, the characteristics of E/M hybrid cells, their importance in tumor progression, and the key regulators in the tumor microenvironment that support this phenotype are still poorly understood, especially in ovarian cancer. In this study, we aim to dissect and characterize the different steps during the transition of cancer cells into the E/M hybrid state. Our data show that once the cells enter the E/M hybrid state, they acquire stable anoikis resistance, invasive capacity, and tumorigenic potential. We identified the hepatocyte growth factor (HGF)/c-MET pathway as a major driver that pushes cells in the E/M hybrid state. ABSTRACT: Purpose: Cancer progression, invasiveness, and metastatic potential have been associated with the activation of the cellular development program known as epithelial-to-mesenchymal transition (EMT). This process is known to yield not only mesenchymal cells, but instead an array of cells with different degrees of epithelial and mesenchymal phenotypes with high plasticity, usually referred to as E/M hybrid cells. The characteristics of E/M hybrid cells, their importance in tumor progression, and the key regulators in the tumor microenvironment that support this phenotype are still poorly understood. Methods: In this study, we established an in vitro model of EMT and characterized the different stages of differentiation, allowing us to identify the main genomic signature associated with the E/M hybrid state. Results: We report that once the cells enter the E/M hybrid state, they acquire stable anoikis resistance, invasive capacity, and tumorigenic potential. We identified the hepatocyte growth factor (HGF)/c-MET pathway as a major driver that pushes cells in the E/M hybrid state. Conclusions: Herein, we provide a detailed characterization of the signaling pathway(s) promoting and the genes associated with the E/M hybrid state.