RT Journal Article
SR Electronic
T1 Applied stretch initiates directional invasion through the action of Rap1 GTPase as a tension sensor
JF Journal of Cell Science
JO J. Cell Sci.
FD The Company of Biologists Ltd
SP 152
OP 163
DO 10.1242/jcs.180612
VO 130
IS 1
A1 Freeman, Spencer A.
A1 Christian, Sonja
A1 Austin, Pamela
A1 Iu, Irene
A1 Graves, Marcia L.
A1 Huang, Lin
A1 Tang, Shuo
A1 Coombs, Daniel
A1 Gold, Michael R.
A1 Roskelley, Calvin D.
YR 2017
UL http://jcs.biologists.org/content/130/1/152.abstract
AB 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.