Switch-like enhancement of epithelial-mesenchymal transition by YAP through feedback regulation of WT1 and small Rho-family GTPases

TL;DR

This study reveals how nano-scale extracellular matrix topography influences epithelial-mesenchymal transition (EMT) via YAP mechano-sensitivity and feedback loops involving WT1 and Rho GTPases, promoting invasive cell behavior.

Contribution

It uncovers novel feedback mechanisms regulating YAP activity that induce a switch-like EMT response, linking extracellular cues to cell invasion.

Findings

Nano-scale ECM topography affects EMT dynamics.

YAP mechano-sensitivity controls feedback loops involving WT1 and Rho GTPases.

YAP-dependent feedback induces a switch-like increase in EMT markers.

Abstract

Collective cell migration is a hallmark of developmental and patho-physiological states, including wound healing and invasive cancer growth. The integrity of the expanding epithelial sheets can be influenced by extracellular cues, including cell-cell and cell-matrix interactions. We show the nano-scale topography of the extracellular matrix underlying epithelial cell layers can have a strong effect on the speed and morphology of the fronts of the expanding sheet triggering epithelial-mesenchymal transition (EMT). We further demonstrate that this behavior depends on the mechano-sensitivity of the transcription regulator YAP and two new feedback cross-regulation mechanisms: through Wilms Tumor-1 and E-cadherin, loosening cell-cell contacts, and through Rho GTPase family proteins, enhancing cell migration. These YAP-dependent regulatory feedback loops result in a switch-like change in the signaling and expression of EMT-related markers, leading to a robust enhancement in invasive epithelial sheet expansion, which might lead to a poorer clinical outcome in renal and other cancers.