Boolean modeling of mechanosensitive Epithelial to Mesenchymal Transition and its reversal

The significance of biophysical modulators of the Epithelial to Mesenchymal Transition is demonstrated by experiments that show EMT on nano-patterned ECM without biochemical signals, or stiffness-induced / shape-dependent induction of EMT transcription factors. Yet, current models focus on biochemical triggers without addressing the mechanosensitive drivers of EMT. Here we built a Boolean model of EMT triggered by crosstalk between mechanosensing and mitogens. Our model reproduces epithelial, hybrid E/M and mesenchymal phenotypes, the role of autocrine TGFβ signaling in maintaining mesenchymal cells in the absence of biomechanical drivers, inhibition of proliferation by TGFβ, and its apoptotic effects on soft ECM. We offer testable predictions on the density-dependence and molecular drivers of partial EMT and the tug of war between mitosis and the stability hybrid E/M state. Our model serves as a stepping-stone towards modeling the effects of the biomechanical environment on cancer cell stemness linked to the hybrid E/M state, as well as the mutually inhibitory crosstalk between EMT and senescence.