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

JinSeok Park, Deok-Ho Kim, Sagar R. Shah, Hong-Nam Kim, Kshitiz, Peter Kim, Alfredo Quiñones-Hinojosa () and Andre Levchenko ()
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JinSeok Park: Yale University
Deok-Ho Kim: University of Washington
Sagar R. Shah: The Johns Hopkins University School of Medicine
Hong-Nam Kim: Korea Institute of Science and Technology
Kshitiz: Yale University
Peter Kim: University of Washington
Alfredo Quiñones-Hinojosa: Mayo Clinic
Andre Levchenko: Yale University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Collective cell migration occurs in many patho-physiological states, including wound healing and invasive cancer growth. The integrity of the expanding epithelial sheets depends on extracellular cues, including cell-cell and cell-matrix interactions. We show that the nano-scale topography of the extracellular matrix underlying epithelial cell layers can strongly affect the speed and morphology of the fronts of the expanding sheet, triggering partial and complete epithelial-mesenchymal transitions (EMTs). We further demonstrate that this behavior depends on the mechano-sensitivity of the transcription regulator YAP and two new YAP-mediated cross-regulating feedback mechanisms: Wilms Tumor-1-YAP-mediated downregulation of E-cadherin, loosening cell-cell contacts, and YAP-TRIO-Merlin mediated regulation of Rho GTPase family proteins, enhancing cell migration. These YAP-dependent feedback loops result in a switch-like change in the signaling and the expression of EMT-related markers, leading to a robust enhancement in invasive cell spread, which may lead to a worsened clinical outcome in renal and other cancers.

Date: 2019
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DOI: 10.1038/s41467-019-10729-5

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