Phenotypic plasticity of ovarian carcinoma cells lead to higher resistance to treatment when cultivated in collagen-based 3D model

Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells transform into mesenchymal cells by change in the expression and metabolism profile and acquire the ability to invade. The cultivation conditions of cancer cells can provoke EMT, which in turn can affect their resistance to therapy. In this work, we compared the amount of contact proteins in the human ovarian adenocarcinoma cell lines SKOV-3 and SKOV-3.ip cultured in monolayers, tumor spheroids, and collagen I hydrogels. 3D models of both studied cell lines are characterized by extremely low expression of the main adhesive molecule E-cadherin and demonstrated a simultaneous decrease in desmosomal protein desmoglein-2, gap junction protein connexin-43, and tight junction proteins occludin and ZO-1. Culturing cells in a hydrogel led to the more manifested phenotypic changes and also resulted in higher resistance to treatment with doxorubicin or with a targeted protein toxin specific for the HER2 receptor. A decrease in the level of contact proteins during cell cultivation in a 3D model can be a sign of the acquisition of a more mesenchymal phenotype by tumor cells. We believe that the epithelial-mesenchymal transition may be induced by three-dimensional cultivation and altered features of the microenvironment, which, in turn, can change the responsivity to treatment.

This research was funded by the Russian Science Foundation (project No. 19-74-20168)