한빛사 논문
JinSeok Park1,6, Deok-Ho Kim2,6, Sagar R. Shah3,4, Hong-Nam Kim5, Kshitiz1, Peter Kim2, Alfredo Quiñones-Hinojosa4,* & Andre Levchenko1,*
1 Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT 06520, USA. 2 Department of Bioengineering and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA. 3 Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. 4 Department of Neurologic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA. 5 Center for BioMicrosystems, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea. 6These authors contributed equally: JinSeok Park, Deok-Ho Kim.
*Correspondence and requests for materials should be addressed to A.Q-H. or to A.L.
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.
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