title: Applied stretch initiates directional invasion through the action of Rap1 GTPase as a tension sensor.
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.
authors.affiliation: Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Spencer A
authors.initials: SA
authors.lastname: Freeman
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.|Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Sonja
authors.initials: S
authors.lastname: Christian
authors.affiliation: Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada.|Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Pamela
authors.initials: P
authors.lastname: Austin
authors.affiliation: Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada.|Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Irene
authors.initials: I
authors.lastname: Iu
authors.affiliation: Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada.|Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Marcia L
authors.initials: ML
authors.lastname: Graves
authors.affiliation: Department of Electrical Engineering, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Lin
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Electrical Engineering, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Shuo
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Mathematics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Coombs
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.|Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Gold
authors.affiliation: Life Sciences Institute, University of British Columbia, 2350 Health Sciences Road, Vancouver, British Columbia, V6T 1Z3, Canada roskelly@mail.ubc.ca.|Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Calvin D
authors.identifier: 0000-0003-0939-8900
authors.initials: CD
authors.lastname: Roskelley
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D002449:Cell Aggregation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D005782:Gels; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007365:Intercellular Junctions / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D058105:Polymerization; D055550:Protein Stability; D011554:Pseudopodia / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D016596:Vinculin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D050719:Crk-Associated Substrate Protein; D005782:Gels; D016023:Integrins; D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D016596:Vinculin; D006160:Guanosine Triphosphate; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D020830:rac1 GTP-Binding Protein; D020827:rap1 GTP-Binding Proteins
keywords: Actin cytoskeleton; Focal adhesions; Integrin; Mechanotransduction; Rap GTPases; Talin; Vinculin