title: Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis.
abstract: 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.
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: Hon S
authors.initials: HS
authors.lastname: Leong
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Robertson
authors.affiliation: Department of Oncology, University of Alberta, 5-142C Katz Group Building, Edmonton AB T6G 2E1, Canada.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Stoletov
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Leith
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Chin
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Chien
authors.affiliation: London Regional Cancer Program, Cancer Research Laboratory Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: M Nicole
authors.initials: MN
authors.lastname: Hague
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: Amber
authors.initials: A
authors.lastname: Ablack
authors.affiliation: Department of Oncology, University of Alberta, 5-142C Katz Group Building, Edmonton AB T6G 2E1, Canada.
authors.forename: Katia
authors.initials: K
authors.lastname: Carmine-Simmen
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: Victor A
authors.initials: VA
authors.lastname: McPherson
authors.affiliation: London Regional Cancer Program, Cancer Research Laboratory Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: Carl O
authors.initials: CO
authors.lastname: Postenka
authors.affiliation: London Regional Cancer Program, Cancer Research Laboratory Program, 790 Commissioners Road East, London ON N6A 4L6, Canada; Departments of Biochemistry, Oncology, and Surgery, Western University, London, ON N6A 5C1, Canada.
authors.forename: Eva A
authors.initials: EA
authors.lastname: Turley
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Collaborative Life Sciences Building, 2750 SW Moody Avenue, Portland, OR 97239, USA.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Courtneidge
authors.affiliation: London Regional Cancer Program, Cancer Research Laboratory Program, 790 Commissioners Road East, London ON N6A 4L6, Canada.
authors.forename: Ann F
authors.initials: AF
authors.lastname: Chambers
authors.affiliation: Department of Oncology, University of Alberta, 5-142C Katz Group Building, Edmonton AB T6G 2E1, Canada. Electronic address: jdlewis@ualberta.ca.
authors.forename: John D
authors.initials: JD
authors.lastname: Lewis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000187:drug effects / Q000378:metabolism*; D002642:Chick Embryo; D051356:Cortactin / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000502:physiology; D028044:Phosphate-Binding Proteins; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D057688:Transcellular Cell Migration
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D051356:Cortactin; C114235:Fish protein, mouse; D028044:Phosphate-Binding Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C541985:Tks4 protein, mouse; C515233:saracatinib; D053511:Matrix Metalloproteinase 14