Mean residence times of TF-TF and TF-miRNA toggle switches.

Toggle switch networks are the simplest possible circuits with the ability of making a decision related to cell differentiation during embryonic development and disease progression. A common occurrence of toggle switch circuits is in the epithelial-mesenchymal transition (EMT) and its reverse, the mesenchymal-epithelial transition (MET), pathways which play key roles in phenotypic plasticity during cancer metastasis and therapy resistance. Recent studies have shown that the cells attaining one or more hybrid epithelial/mesenchymal (E/M) phenotypes during EMT/MET are more aggressive than those in either the epithelial or mesenchymal phenotype. In this work we studied the stability of each phenotype for different toggle switch circuits. We considered two-component toggle switch networks comprising either two mutually inhibiting transcription factors (TF-TF) or a TF-microRNA (TF-miR) chimera pair, and from Langevin dynamics, we determined the mean residence time (MRT) of cell phenotypes. MRT can be considered to be an indicator of stability in each cell phenotype and we showed that by replacing one of the TFs of the TF-TF toggle switch with miRNA generically stabilizes the hybrid phenotype. However, in the absence [presence] of a monostable hybrid state, the miRNA with faster [slower] degradation will make the hybrid state more probable. These results help to understand the implications of TF-TF and TF-miR circuits in the dynamics of cell fate decisions.