Filamin-ETV4/5 acts as mechanosensor-mechanotransducer axis that drives cell competition-mediated elimination of transformed cells.

Abstract

Cell competition is a fundamental surveillance mechanism that preserves epithelial integrity by eliminating aberrant "loser" cells through interactions with surrounding "winner" cells. However, how winner cells sense and eliminate transformed neighbours remains poorly understood. Here, using a synNotch-based transcriptomic screen, we identify a mechanosensor-mechanotransducer axis linking the actin crosslinker filamin to the ETV4/5-PRKG2 pathway that mediates extrusion of oncogenically transformed cells through cell competition. Within an epithelial monolayer, transformed cells increase their volume, inducing membrane stretching. In adjacent normal cells, filamin senses the increased membrane tension and triggers activation of ETV4/5. Activated ETV4/5 then upregulate PRKG2, which promotes volume expansion of normal cells, consequently pushing back and driving the extrusion of transformed cells. These findings reveal that dynamic changes in cell volume can trigger mechanotransduction-driven cell competition, uncovering a fundamental pathway by which epithelial tissues maintain homoeostasis and defend against oncogenic transformation.