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Worrying drives cell migration in mechanically unrestrained environments

Erik S. Welf, Meghan K. Driscoll, Etai Sapoznik, Vasanth S. Murali, Andrew Weems, Minna Roh-Johnson, Kevin M. Dean, Reto Fiolka, Gaudenz Danuser
doi: https://doi.org/10.1101/2020.11.09.372912
Erik S. Welf
1Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX
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Meghan K. Driscoll
1Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX
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Etai Sapoznik
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX
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Vasanth S. Murali
1Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX
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Andrew Weems
1Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX
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Minna Roh-Johnson
3Department of Biochemistry, School of Medicine, University of Utah, Salt Lake City, UT
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Kevin M. Dean
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX
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Reto Fiolka
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX
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  • For correspondence: Gaudenz.Danuser@UTSouthwestern.edu Reto.Fiolka@UTSouthwestern.edu
Gaudenz Danuser
1Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX
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  • For correspondence: Gaudenz.Danuser@UTSouthwestern.edu Reto.Fiolka@UTSouthwestern.edu
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Abstract

Migratory cells employ numerous strategies to navigate the very diverse 3D microenvironments found in vivo. These strategies are subdivided into those that create space by pericellular proteolysis of extracellular matrix (ECM) proteins and those that navigate existing spaces. We find that cells can employ an alternative mechanism by digging tunnels through 3D collagen networks without extracellular proteolysis. This is accomplished by persistent polarization of large dynamic membrane blebs at the closed end of the tunnel that repeatedly agitate the collagen, a process we termed mechanical worrying. We find that this agitation promotes breakage and internalization of collagen at the cell front along with extracellular fluid in a macropinocytosis-driven manner. Membrane blebs are short-lived relative to the timescale of migration, and thus their polarization is critical for persistent ablation of the ECM. We find that sustained interactions between the collagen at the cell front and small but persistent cortical adhesions induce PI-3 Kinase (PI3K) signaling that drives polarized bleb enlargement via the Rac1 – Arp2/3 pathway. This defines a mechanism for the reinforcement of bleb expansion against load, which enables precise ablation of mechanically unrestrained environments, such as those encountered in very compliant tissue.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 09, 2020.
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Worrying drives cell migration in mechanically unrestrained environments
Erik S. Welf, Meghan K. Driscoll, Etai Sapoznik, Vasanth S. Murali, Andrew Weems, Minna Roh-Johnson, Kevin M. Dean, Reto Fiolka, Gaudenz Danuser
bioRxiv 2020.11.09.372912; doi: https://doi.org/10.1101/2020.11.09.372912
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Worrying drives cell migration in mechanically unrestrained environments
Erik S. Welf, Meghan K. Driscoll, Etai Sapoznik, Vasanth S. Murali, Andrew Weems, Minna Roh-Johnson, Kevin M. Dean, Reto Fiolka, Gaudenz Danuser
bioRxiv 2020.11.09.372912; doi: https://doi.org/10.1101/2020.11.09.372912

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