Invadopodia Are Required for Cancer Cell Extravasation and Are a Therapeutic Target for Metastasis
Hon S. Leong,
Amy E. Robertson,
Konstantin Stoletov,
Sean J. Leith,
Curtis A. Chin,
Andrew E. Chien,
M. Nicole Hague,
Amber Ablack,
Katia Carmine-Simmen,
Victor A. McPherson,
Carl O. Postenka,
Eva A. Turley,
Sara A. Courtneidge,
Ann F. Chambers,
John D. Lewis
Affiliations
Hon S. Leong
Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
Amy E. Robertson
Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
Konstantin Stoletov
Department of Oncology, University of Alberta, 5-142C Katz Group Building, Edmonton AB T6G 2E1, Canada
Sean J. Leith
Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
Curtis A. Chin
Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
Andrew E. Chien
Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
M. Nicole Hague
London Regional Cancer Program, Cancer Research Laboratory Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
Amber Ablack
Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
Katia Carmine-Simmen
Department of Oncology, University of Alberta, 5-142C Katz Group Building, Edmonton AB T6G 2E1, Canada
Victor A. McPherson
Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
Carl O. Postenka
London Regional Cancer Program, Cancer Research Laboratory Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
Eva A. Turley
London Regional Cancer Program, Cancer Research Laboratory Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
Sara A. Courtneidge
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Collaborative Life Sciences Building, 2750 SW Moody Avenue, Portland, OR 97239, USA
Ann F. Chambers
London Regional Cancer Program, Cancer Research Laboratory Program, 790 Commissioners Road East, London ON N6A 4L6, Canada
John D. Lewis
Department of Oncology, University of Alberta, 5-142C Katz Group Building, Edmonton AB T6G 2E1, Canada
Tumor cell extravasation is a key step during cancer metastasis, yet the precise mechanisms that regulate this dynamic process are unclear. We utilized a high-resolution time-lapse intravital imaging approach to visualize the dynamics of cancer cell extravasation in vivo. During intravascular migration, cancer cells form protrusive structures identified as invadopodia by their enrichment of MT1-MMP, cortactin, Tks4, and importantly Tks5, which localizes exclusively to invadopodia. Cancer cells extend invadopodia through the endothelium into the extravascular stroma prior to their extravasation at endothelial junctions. Genetic or pharmacological inhibition of invadopodia initiation (cortactin), maturation (Tks5), or function (Tks4) resulted in an abrogation of cancer cell extravasation and metastatic colony formation in an experimental mouse lung metastasis model. This provides direct evidence of a functional role for invadopodia during cancer cell extravasation and distant metastasis and reveals an opportunity for therapeutic intervention in this clinically important process.
