Prostate cancer cell-platelet bidirectional signaling promotes calcium mobilization, invasion and apoptotic resistance via distinct receptor-ligand pairs

ABSTRACT: Platelets play a crucial role in cancer and thrombosis. The receptor-ligand repertoire mediating prostate cancer (PCa) cell-platelet interactions have not been fully elucidated. Microvilli emanating from the plasma membrane of PCa cell lines (RC77 T/E, MDA PCa 2b) directly contacted individual platelets and platelet aggregates, thereby stimulating calcium mobilization in platelets and promoting translocation of P-selectin and integrin aIIbb3 onto the platelet surface. Platelets in turn dose-dependently stimulated PCa cell invasion and apoptotic resistance. PCa cells were exceedingly sensitive to activation by platelets, occurring at platelet:PCa cell ratios ~20,000-fold lower than normally encountered in blood. Candidate platelet-PCa cell signaling axis partners responsible for these cellular events were identified by RNA-Seq and could be broadly divided into 4 categories: i) integrin-ligand, ii) EPH receptor-ephrin, iii) immune checkpoint receptor-ligand, and iv) miscellaneous receptor-ligand interactions. PCa cell-stimulated calcium mobilization was mediated by a fibronectin1 (FN1; PCa side)-aIIbb3 (platelet side) axis. Reciprocally, platelet-stimulated PCa cell invasion was facilitated by a CD55 (platelet side)-adhesion G-protein coupled receptor E5 (ADGRE5; PCa side) axis, with contribution from platelet cytokines CCL3L1 and IL32. Platelet-stimulated PCa cell apoptotic resistance relied on ephrin-EPH receptor and lysophosphatidic acid (LPA)-LPA receptor (LPAR) signaling. Of the participating partners, FN1 and LPAR3 overexpression was observed in PCa specimens compared to normal prostate, while high expression of CCR1 (CCL3L1 receptor), EPHA1 and LPAR5 in PCa was associated with poor patient survival. These findings emphasize that non-overlapping receptor-ligand pairs participate in oncogenesis and thrombosis, highlighting the complexity of any contemplated clinical intervention strategy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216942 | GEO | 2022/11/05

REPOSITORIES: GEO