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Nat Commun. 2019 Jun 26;10(1):2797. doi: 10.1038/s41467-019-10729-5.

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

Author information

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.
6
Department of Neurologic Surgery, Mayo Clinic, Jacksonville, FL, 32224, USA. Quinones-Hinojosa.Alfredo@mayo.edu.
7
Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, New Haven, CT, 06520, USA. andre.levchenko@yale.edu.

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.

PMID:
31243273
PMCID:
PMC6594963
DOI:
10.1038/s41467-019-10729-5
[Indexed for MEDLINE]
Free PMC Article

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