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