Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell-derived ADAM9

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 alpha 6 beta 1 on platelets markedly decreases experimental and spontaneous lung metastasis. In vitro and in vivo assays reveal that human and mouse platelet alpha 6 beta 1 supports platelet adhesion to various types of cancer cells. Using a knockdown approach, we identified ADAM9 as the major counter receptor of alpha 6 beta 1 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 alpha 6 beta 1. In vivo studies showed that the interplay between platelet alpha 6 beta 1 and tumor cell-expressed ADAM9 promotes efficient lung metastasis. The integrin alpha 6 beta 1-dependent platelet-tumor cell interaction induces platelet activation and favors the extravasation process of tumor cells. Finally, we demonstrate that a pharmacological approach targeting alpha 6 beta 1 efficiently impairs tumor metastasis through a platelet-dependent mechanism. Our study reveals a mechanism by which platelets promote tumor metastasis and suggests that integrin alpha 6 beta 1 represents a promising target for antimetastatic therapies.