Modeling the influence of cell-cell contact and TGF-β signaling on the epithelial mesenchymal transition in MCF7 breast carcinoma cells

Abstract

The epithelial mesenchymal transition (EMT) is a process by which cells lose their adhesive nature and gain the migratory properties associated with mesenchymal cells. This transition allows cells to migrate away from a primary tumor while maintaining their newly acquired invasive behavior, suggesting that there is a bistable switch between the epithelial and mesenchymal phenotypes. In recent experimental work, we found evidence of this bistability in the MCF7 breast carcinoma cell line (Gasior et al., 2019). Underlying the complex processes governing EMT, we identify a feedback loop between E-cadherin, a protein involved in cellular adhesion, and Slug, a transcription factor that is upregulated during EMT. Here, we present a simple mathematical model that examines the relationship between E-cadherin and Slug in response to pro-epithelial and pro-mesenchymal factors, cell-cell contact and TGF-β, respectively. We hypothesize that cell-cell contact is a critical component in the transition from the epithelial to the mesenchymal phenotype and that it is possible to initiate EMT with the loss of cell-cell contact or the activation of the TGF-β signaling pathway. We propose a reversible bistable switch in response to a loss of cell-cell contact but an irreversible bistable switch when the cell is exposed to TGF-β. Taken together, this model shows that acquiring and retaining invasive behavior by cells with high levels of cell-cell contact is not impossible but, instead, depends on the cooperation between the two switches. The predictions of this model for E-cadherin and Slug levels were compared against relative gene expression data from our recent experiments with MCF7 cells (Gasior et al., 2019). Our model works well to predict E-cadherin and Slug mRNA expression in low confluence experiments, while also highlighting issues that arise when comparing experimental results to theoretical predictions.

Keywords: Bistable switch; Breast carcinoma; Cell–cell contact; Epithelial mesenchymal transition; TGF-β.