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arXiv · 1704.01693

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

JinSeok Park·Deok-Ho Kim·Sagar R. Shah·Hong-Nam Kim·Kshitiz·David Ellison·Peter Kim·Kahp-Yang Suh·Alfredo Quiñones-Hinojosa·Andre Levchenko
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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.

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JinSeok Park, Deok-Ho Kim, Sagar R. Shah, Hong-Nam Kim, Kshitiz, David Ellison, Peter Kim, Kahp-Yang Suh, Alfredo Quiñones-Hinojosa, Andre Levchenko. 2017-04-06. Switch-like enhancement of epithelial-mesenchymal transition by YAP through feedback regulation of WT1 and small Rho-family GTPases. https://doi.org/10.1038/s41467-019-10729-5

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