Boolean modeling of mechanosensitive epithelial to mesenchymal transition and its reversal
Emmalee Sullivan,
Marlayna Harris,
Arnav Bhatnagar,
Eric Guberman,
Ian Zonfa,
Erzsébet Ravasz Regan
Affiliations
Emmalee Sullivan
Biochemistry and Molecular Biology, The College of Wooster, Wooster, OH 44691, USA; Ohio University Heritage College of Osteopathic Medicine, Cleveland, OH44122, USA
Marlayna Harris
Biochemistry and Molecular Biology, The College of Wooster, Wooster, OH 44691, USA; Stanford University School of Medicine, Stanford, CA94305, USA
Arnav Bhatnagar
Biochemistry and Molecular Biology, The College of Wooster, Wooster, OH 44691, USA; Molecular, Cellular, and Developmental Biology, UC Santa Barbara, Goleta, CA93117, USA
Eric Guberman
Biochemistry and Molecular Biology, The College of Wooster, Wooster, OH 44691, USA; Boston University School of Public Health, Boston, MA02118, USA
Ian Zonfa
Biochemistry and Molecular Biology, The College of Wooster, Wooster, OH 44691, USA; Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
Erzsébet Ravasz Regan
Biochemistry and Molecular Biology, The College of Wooster, Wooster, OH 44691, USA; Corresponding author
Summary: The significance of biophysical modulators of the epithelial to mesenchymal transition (EMT) is demonstrated by experiments that document full EMT on stiff, nano-patterned substrates in the absence of biochemical induction. Yet, current models focus on biochemical triggers of EMT without addressing its mechanosensitive nature. Here, we built a Boolean model of EMT triggered by mechanosensing – mitogen crosstalk. Our model reproduces epithelial, hybrid E/M and mesenchymal phenotypes, the role of autocrine TGFβ signaling in maintaining mesenchymal cells in the absence of external drivers, inhibition of proliferation by TGFβ, and its apoptotic effects on soft ECM. We offer testable predictions on the density-dependence of partial EMT, its molecular drivers, and the conflict between mitosis and hybrid E/M stability. Our model opens the door to 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.
