Stability and mean residence times for hybrid epithelial/mesenchymal phenotype.

Cancer metastasis and drug resistance remain unsolved clinical challenges. A phenotypic transition
 that is often implicated in both these processes is Epithelial-Mesenchymal Transition (EMT) during
 which epithelial cells weaken their cell-cell adhesion and gain traits of migration and invasion, typical
 of mesenchymal cells. However, recent studies indicate that apart from these two states, cells can also
 exist in one or more hybrid E/M state(s) which plays an aggressive role in progression of the disease.
 Furthermore, computational and experimental studies have identified a variety of phenotypic stability
 factors (PSF) that stabilizes the hybrid E/M state(s) and can increase disease aggressiveness. In this
 work, we study EMT regulatory networks, in the presence of different PSFs, as dynamical systems
 subjected to random fluctuations. The cells thus explore different stable E, M, E/M states in the
 potential landscape and our aim is to quantify the residence time in each of these states. Our stochastic
 simulations indicate an universal feature that the mean residence time (MRT) in the hybrid E/M state
 is enhanced in the presence of PSFs. We demonstrate that the feature is consistent for a variety of
 PSFs, namely, GRHL2, OV OL, ∆N p63α, miR - 145/OCT 4, participating in the core EMT regulatory
 network and for different operating conditions. Our results reveal potential targets for pushing cells out
 of a hybrid E/M state and thus halting cancer progression.