YAP/TAZ cytoskeletal remodelling is driven by mechanotactic and electrotactic cues

Abstract

Cells respond dynamically to multiple cues in complex microenvironments, which influence their behaviour, function, and molecular pathways. Despite recent advances, understanding cell interactions in such environments remains challenging. While biophysical cues are recognized for interacting with mechano-transduction proteins like YAP/TAZ, their role under glioblastoma electrotaxis is unclear. Our study investigates the functional role of mechano-transduction proteins under a physiological electric field (EF) with different rigidities. EF exposure highlights rigidity-dependent responses involving focal adhesion, cytoskeletal remodelling and YAP/TAZ coactivators relocation, showing to induce a shuttling in a rigidity-dependent manner. Further inhibition of PI3K/Akt and pharmacologically disrupting YAP/TAZ-TEAD interaction was shown to induce marked cytoskeletal remodelling under EFs. Our work characterises the therapeutic opportunities and limitations of EFs and uncovers the intricate interplay of physical cues and molecular signalling pathways in glioblastoma, offering potential insights for the development of therapeutic interventions in the future.