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Research Article
Applied stretch initiates directional invasion through the action of Rap1 GTPase as a tension sensor
Spencer A. Freeman, Sonja Christian, Pamela Austin, Irene Iu, Marcia L. Graves, Lin Huang, Shuo Tang, Daniel Coombs, Michael R. Gold, Calvin D. Roskelley
Journal of Cell Science 2017 130: 152-163; doi: 10.1242/jcs.180612
Spencer A. Freeman
1Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada
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Sonja Christian
2Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada
3Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada
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Pamela Austin
3Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada
4Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada
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Irene Iu
3Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada
4Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada
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Marcia L. Graves
3Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada
4Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada
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Lin Huang
5Department of Electrical Engineering, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada
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Shuo Tang
5Department of Electrical Engineering, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada
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Daniel Coombs
6Department of Mathematics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada
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Michael R. Gold
2Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada
3Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada
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Calvin D. Roskelley
3Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada
4Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada
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  • For correspondence: roskelly@mail.ubc.ca
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ABSTRACT

Although it is known that a stiffening of the stroma and the rearrangement of collagen fibers within the extracellular matrix facilitate the movement of tumor cells away from the primary lesion, the underlying mechanisms responsible are not fully understood. We now show that this invasion, which can be initiated by applying tensional loads to a three-dimensional collagen gel matrix in culture, is dependent on the Rap1 GTPases (Rap1a and Rap1b, referred to collectively as Rap1). Under these conditions Rap1 activity stimulates the formation of focal adhesion structures that align with the tensional axis as single tumor cells move into the matrix. These effects are mediated by the ability of Rap1 to induce the polarized polymerization and retrograde flow of actin, which stabilizes integrins and recruits vinculin to preformed adhesions, particularly those near the leading edge of invasive cells. Rap1 activity also contributes to the tension-induced collective invasive elongation of tumor cell clusters and it enhances tumor cell growth in vivo. Thus, Rap1 mediates the effects of increased extracellular tension in multiple ways that are capable of contributing to tumor progression when dysregulated.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    S.A.F., S.T., D.C., M.R.G, and C.D.R conceived and designed experimental systems; S.A.F, S.C., P.A., I.I., M.L.G., and L.H. performed experiments; S.A.F, S.C., P.A., I.I., and M.L.G. analysed the data; S.A.F., S.C., P.A., M.R.G., and C.D.R. wrote the manuscript.

  • Funding

    This work was supported by grants from the Canadian Institutes of Health Research [grant number MOP-10463 to M.R.G. and C.D.R.]; and the Natural Sciences and Engineering Research Council of Canada [grant number RGPIN-1501-04611 to D.C.].

  • Supplementary information

    Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.180612.supplemental

  • Received September 24, 2015.
  • Accepted May 13, 2016.
  • © 2017. Published by The Company of Biologists Ltd
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Keywords

  • Mechanotransduction
  • Rap GTPases
  • Focal adhesions
  • Actin cytoskeleton
  • Talin
  • Vinculin
  • integrin

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Research Article
Applied stretch initiates directional invasion through the action of Rap1 GTPase as a tension sensor
Spencer A. Freeman, Sonja Christian, Pamela Austin, Irene Iu, Marcia L. Graves, Lin Huang, Shuo Tang, Daniel Coombs, Michael R. Gold, Calvin D. Roskelley
Journal of Cell Science 2017 130: 152-163; doi: 10.1242/jcs.180612
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Research Article
Applied stretch initiates directional invasion through the action of Rap1 GTPase as a tension sensor
Spencer A. Freeman, Sonja Christian, Pamela Austin, Irene Iu, Marcia L. Graves, Lin Huang, Shuo Tang, Daniel Coombs, Michael R. Gold, Calvin D. Roskelley
Journal of Cell Science 2017 130: 152-163; doi: 10.1242/jcs.180612

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