Coupled Reversible and Irreversible Bistable Switches Underlying TGF-\beta-induced Epithelial to Mesenchymal Transition

TL;DR

This paper presents a mathematical model showing that TGF-eta-induced EMT involves coupled reversible and irreversible bistable switches, explaining the sequential transition from epithelial to mesenchymal states and predicting dynamic behaviors.

Contribution

It introduces a novel coupled bistable switch model that mechanistically explains EMT regulation and response to TGF-eta, integrating feedback loops and noise robustness.

Findings

EMT occurs via a two-step process with partial and full transition.

Reversible switch is governed by SNAIL1/miR-34 feedback loop.

Irreversible switch is controlled by ZEB/miR-200 feedback loop.

Abstract

Epithelial to mesenchymal transition (EMT) plays important roles in embryonic development, tissue regeneration and cancer metastasis. While several feedback loops have been shown to regulate EMT, it remains elusive how they coordinately modulate EMT response to TGF-\beta treatment. We construct a mathematical model for the core regulatory network controlling TGF-\beta-induced EMT. Through deterministic analyses and stochastic simulations, we show that EMT is a sequential two-step program that an epithelial cell first transits to partial EMT then to the mesenchymal state, depending on the strength and duration of TGF-\beta stimulation. Mechanistically the system is governed by coupled reversible and irreversible bistable switches. The SNAIL1/miR-34 double negative feedback loop is responsible for the reversible switch and regulates the initiation of EMT, while the ZEB/miR-200 feedback loop is accountable for the irreversible switch and controls the establishment of the mesenchymal state. Furthermore, an autocrine TGF-\beta/miR-200 feedback loop makes the second switch irreversible, modulating the maintenance of EMT. Such coupled bistable switches are robust to parameter variation and molecular noise. We provide a mechanistic explanation on multiple experimental observations. The model makes several explicit predictions on hysteretic dynamic behaviors, system response to pulsed stimulation and various perturbations, which can be straightforwardly tested.