Anticipating critical transitions in epithelial-hybrid-mesenchymal cell-fate determination

Abstract

In the vicinity of a tipping point, critical transitions occur when small changes in an input condition causes sudden, large and often irreversible changes in the state of a system. Many natural systems ranging from ecosystems to molecular biosystems are known to exhibit critical transitions in their response to stochastic perturbations. In diseases, an early prediction of upcoming critical transitions from a healthy to a disease state by using early warning signals is of prime interest due to potential application in forecasting disease onset. Here, we analyze cell-fate transitions between different phenotypes (epithelial, hybrid epithelial/mesenchymal (E/M) and mesenchymal states) that are implicated in cancer metastasis and chemoresistance. These transitions are mediated by a mutually inhibitory feedback loop microRNA-200/ZEB driven by the levels of transcription factor SNAIL. We find that the proximity to tipping points enabling these transitions among different phenotypes can be captured by critical slowing down based early warning signals, calculated from the trajectory of ZEB mRNA level. Further, the basin stability analysis reveals the unexpectedly large basin of attraction for a hybrid E/M phenotype. Finally, we identified mechanisms that can potentially elude the transition to a hybrid E/M phenotype. Overall, our results unravel the early warning signals that can be used to anticipate upcoming epithelial-hybrid-mesenchymal transitions. With the emerging evidence about the hybrid E/M phenotype being a key driver of metastasis, drug resistance, and tumor relapse; our results suggest ways to potentially evade these transitions, reducing the fitness of cancer cells and restricting tumor aggressiveness.\n\nSignificance StatementEpithelial-hybrid-mesenchymal transitions play critical roles in cancer metastasis, drug resistance, and tumor relapse. Recent studies have proposed that cells in a hybrid epithelial/mesenchymal phenotype may be more aggressive than those on either end of the spectrum. However, no biomarker to predict upcoming transitions has been identified. Here, we show that critical slowing down based early warning signals can detect sudden transitions among epithelial, hybrid E/M, and mesenchymal phenotypes. Importantly, our results highlight how stable a hybrid E/M phenotype can be, and how can a transition to this state be avoided. Thus, our study provides valuable insights into restricting cellular plasticity en route metastasis.