Pharmacological blockade of GPVI inhibits tumor metastasis. (A-B) C57BL/6 or BALB/c1 WT mice were injected IV with JAQ1 F(abʹ)2 or an irrelevant control F(abʹ)2 antibody, together with the indicated syngeneic tumor cells. (A) MC38 and AT-3 tumor cells are syngenic to a C57BL/6 background and 4T1 tumor cells to a BALB/c1 (B) background, respectively. (C) C57BL/6 mice were injected with MC38 tumor cells, followed after 7 days by injection with JAQ1 F(abʹ)2 or an irrelevant control F(abʹ)2 antibody. Number of experimental lung metastases (A,C) in MC38-, AT-3 (A)-, or 4T1 (B)-injected WT mice was determined 15 days after injection. Data are presented as the mean ± standard deviation (SD); n = 5 (A-C) and n = 6 (B) mice per group. **P < .01; ***P < .001, by unpaired Student t test. (D) Proposed model of the role of platelet GPVI in tumor metastasis. Tumor cells transit from the primary tumor via the blood to form metastases in distant organs. During this process, tumor cells encounter several environmental changes and stimuli, which profoundly impact their metastatic potential. Following entry of tumor cells into the bloodstream, platelet GPVI favors platelet recruitment to circulating tumor cells through its interaction with galectin-3 on the tumor cell surface. Once a stable interaction is established, platelets become activated and can protect tumor cells from hemodynamic shear stress and the host immune system and can favor efficient tumor cell extravasation and subsequent metastasis. The function-blocking anti-GPVI antibody JAQ1 F(Ab’)2 reduces metastasis by preventing platelet–tumor cell cross talk.