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J Cell Biol. 2018 Apr 2;217(4):1485-1502. doi: 10.1083/jcb.201703145. Epub 2018 Feb 5.

Dia1-dependent adhesions are required by epithelial tissues to initiate invasion.

Author information

1
Institute for Biophysical Dynamics, James Franck Institute, and Department of Physics, University of Chicago, Chicago, IL.
2
Committee on Cancer Biology, University of Chicago, Chicago, IL.
3
Ben May Department of Cancer Research, University of Chicago, Chicago, IL.
4
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA.
5
Department of Bioengineering, Stanford University, Stanford, CA.
6
Department of Physics and Astronomy and Department of Biology, University of Rochester, Rochester, NY.
7
Institute for Biophysical Dynamics, James Franck Institute, and Department of Physics, University of Chicago, Chicago, IL gardel@uchicago.edu.

Abstract

Developing tissues change shape and tumors initiate spreading through collective cell motility. Conserved mechanisms by which tissues initiate motility into their surroundings are not known. We investigated cytoskeletal regulators during collective invasion by mouse tumor organoids and epithelial Madin-Darby canine kidney (MDCK) acini undergoing branching morphogenesis in collagen. Use of the broad-spectrum formin inhibitor SMIFH2 prevented the formation of migrating cell fronts in both cell types. Focusing on the role of the formin Dia1 in branching morphogenesis, we found that its depletion in MDCK cells does not alter planar cell motility either within the acinus or in two-dimensional scattering assays. However, Dia1 was required to stabilize protrusions extending into the collagen matrix. Live imaging of actin, myosin, and collagen in control acini revealed adhesions that deformed individual collagen fibrils and generated large traction forces, whereas Dia1-depleted acini exhibited unstable adhesions with minimal collagen deformation and lower force generation. This work identifies Dia1 as an essential regulator of tissue shape changes through its role in stabilizing focal adhesions.

PMID:
29437785
PMCID:
PMC5881494
DOI:
10.1083/jcb.201703145
[Indexed for MEDLINE]
Free PMC Article

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