MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

TLDR

Epithelial–mesenchymal transitions are crucial for embryonic development, wound healing, and cancer metastasis. The study aims to quantitatively understand the core circuitry that translates environmental signals into cell‑fate decisions. A novel model of microRNA‑based coupled chimeric modules was devised, employing a unique theoretical framework for microRNA dynamics. The miR‑200/ZEB module acts as a ternary switch enabling epithelial, mesenchymal, and hybrid phenotypes, and the results suggest strategies to control and reverse epithelial–hybrid–mesenchymal transitions.

Abstract

Significance Epithelial–mesenchymal transitions play crucial roles in embryonic development, wound healing, and cancer metastasis. It is clearly of interest to quantitatively understand the core circuitry that takes input from the cell’s environment to perform this cell-fate decision. We devised a unique model of the microRNA (miR)-based coupled chimeric modules underlying this core circuit; this effort utilizes a unique theoretical framework for treating miR dynamics. We show that the miR-200/ZEB module functions as a ternary switch, allowing not only for the epithelial and mesenchymal phenotypes but also for a hybrid phenotype with mixed characteristics of collective cell migration, as seen in branching morphogenesis and wound closure. Our results provide valuable clues on how to control and reverse epithelial–hybrid–mesenchymal transitions.