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

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