Simulation of multiple microenvironments shows a pivot role of RPTPs on the control of Epithelial-to-Mesenchymal Transition

Abstract

Epithelial-to-Mesenchymal Transition (EMT) is a natural and reversible process involved in embryogenesis, wound healing and thought to participate in the process of metastasis. Multiple signals from the microenvironment have been reported to drive EMT. However, the tight control of this process on physiological scenarios and how it is disrupted during cancer progression is not fully understood. Here, we analysed a regulatory network of EMT accounting for 10 key microenvironment signals focusing on the impact of two cell contact signals on the reversibility of EMT and the stability of resulting phenotypes. The analysis showed that the microenvironment is not enough for stabilizing Hybrid and Amoeboid-like phenotypes, requiring intracellular de-regulations as reported during cancer progression. Our simulations demonstrated that RPTP activation by cell contacts have the potential to inhibit the process of EMT and trigger its reversibility under tissue growth and chronic inflammation scenarios. Simulations also showed that hypoxia inhibits the capacity of RPTPs to control EMT. Our analysis further provided a theoretical explanation for the observed correlation between hypoxia and metastasis under chronic inflammation, and predicted that de-regulations in FAT4 signalling may promote Hybrid stabilization. Taken together, we propose a natural control mechanism of EMT that supports the idea that EMT is tightly regulated by the microenvironment.

Keywords: Cancer; EMT; Metastasis control; Simulation; Tumour microenvironment.