Targeting platelet-mediated CAP-1 upregulation in colorectal cancer: Mechanisms and small-molecule inhibitor development.

Platelets play a critical role in tumor progression and metastasis, yet the mechanisms by which they influence cancer cell behavior remain unclear. In this study, we investigated the interaction between platelets and colorectal cancer (CRC) cells and identified CAP-1 as a key mediator of platelet-induced tumor metastasis. Transcriptomic analyses showed that tumor-educated platelets induced significant gene expression changes in CRC cells, particularly involving pathways related to adhesion and migration. By intersecting upregulated genes in both tumor cells and patient-derived platelets, CAP-1 was identified and functionally validated as a critical gene using in vitro knockdown and in vivo metastasis models. CAP-1 depletion significantly impaired tumor cell migration, adhesion, cytoskeletal organization, and lung metastasis in mice without affecting cell proliferation or viability. A shape-based virtual screening strategy identified small-molecule CAP-1 inhibitors, among which compound CAPib-13 demonstrated strong binding affinity (KD = 2.57 µM), effectively inhibited tumor metastasis in vivo, and showed no significant toxicity. These findings uncover a novel role for CAP-1 in mediating platelet-cancer cell interactions and suggest that CAP-1 inhibition represents a promising therapeutic strategy for metastatic colorectal cancer.