title: Platelet integrinα6β1 controls lung metastasis through direct binding to cancer cell-derived ADAM9.
abstract: Metastatic dissemination of cancer cells, which accounts for 90% of cancer mortality, is the ultimate hallmark of malignancy. Growing evidence suggests that blood platelets have a predominant role in tumor metastasis; however, the molecular mechanisms involved remain elusive. Here, we demonstrate that genetic deficiency of integrin α6β1 on platelets markedly decreases experimental and spontaneous lung metastasis. In vitro and in vivo assays reveal that human and mouse platelet α6β1 supports platelet adhesion to various types of cancer cells. Using a knockdown approach, we identified ADAM9 as the major counter receptor of α6β1 on both human and mouse tumor cells. Static and flow-based adhesion assays of platelets binding to DC-9, a recombinant protein covering the disintegrin-cysteine domain of ADAM9, demonstrated that this receptor directly binds to platelet α6β1. In vivo studies showed that the interplay between platelet α6β1 and tumor cell-expressed ADAM9 promotes efficient lung metastasis. The integrin α6β1-dependent platelet-tumor cell interaction induces platelet activation and favors the extravasation process of tumor cells. Finally, we demonstrate that a pharmacological approach targeting α6β1 efficiently impairs tumor metastasis through a platelet-dependent mechanism. Our study reveals a mechanism by which platelets promote tumor metastasis and suggests that integrin α6β1 represents a promising target for antimetastatic therapies.
authors.affiliation: UMR-S949, INSERM, Etablissement Français du Sang-Alsace, Université de Strasbourg, Strasbourg, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
authors.forename: Elmina
authors.initials: E
authors.lastname: Mammadova-Bach
authors.affiliation: Department of Dermatology and Venerology, University of Cologne, Cologne, Germany.
authors.forename: Paola
authors.initials: P
authors.lastname: Zigrino
authors.affiliation: UMR-S949, INSERM, Etablissement Français du Sang-Alsace, Université de Strasbourg, Strasbourg, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Brucker
authors.affiliation: UMR-S949, INSERM, Etablissement Français du Sang-Alsace, Université de Strasbourg, Strasbourg, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bourdon
authors.affiliation: UMR-S949, INSERM, Etablissement Français du Sang-Alsace, Université de Strasbourg, Strasbourg, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Freund
authors.affiliation: U964, INSERM, UMR 7104, CNRS, Université de Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, Strasbourg, France.
authors.forename: Adèle
authors.initials: A
authors.lastname: De Arcangelis
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
authors.affiliation: INSERM U1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, LabEx Medalis, Strasbourg, France.
authors.forename: Gertaud
authors.initials: G
authors.lastname: Orend
authors.affiliation: UMR-S949, INSERM, Etablissement Français du Sang-Alsace, Université de Strasbourg, Strasbourg, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.affiliation: UMR-S949, INSERM, Etablissement Français du Sang-Alsace, Université de Strasbourg, Strasbourg, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
authors.forename: Pierre Henri
authors.initials: PH
authors.lastname: Mangin
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000818:Animals; D001792:Blood Platelets; D002450:Cell Communication; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D039121:Integrin alpha6beta1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D015539:Platelet Activation; D010973:Platelet Adhesiveness
chemical_list: D039121:Integrin alpha6beta1; D008565:Membrane Proteins; D051722:ADAM Proteins; C098339:ADAM9 protein, human; C498316:Adam9 protein, mouse