In vitro study reveals that pancreatic cancer extracellular vesicles alter platelet proteomes by cargo and lineage, suggesting distinct mechanisms for tumor-induced thrombosis.
The systemic progression of pancreatic ductal adenocarcinoma (PDAC) is tied to a hypercoagulable state, yet early tumor secretome–platelet interactions remain poorly defined. Prevailing models regard platelet education by tumor-derived extracellular vesicles (EVs) as a passive, dose-dependent consequence of vesicle uptake. Using non-malignant ductal epithelial (HPDE), epithelial BxPC-3, and mesenchymal PANC-1 cells, we isolated large (lEVs) and small EVs (sEVs) and assessed their platelet association and proteomic consequences. EV-derived lipid and protein signals did not predict platelet activation. PANC-1 EVs produced the greatest signal acquisition but did not induce P-selectin externalization or phosphatidylserine exposure, whereas BxPC-3 EVs induced both responses. sEV-associated acquisition was actin-sensitive; lEV acquisition was not. Quantitative proteomics showed that donor lineage structured the tumor-educated platelet proteome, whereas lEV exposure induced broad translational and structural signatures. Both PDAC lEV fractions promoted collagen adhesion; however, BxPC-3 lEVs uniquely induced phosphatidylserine exposure, α-granule secretion, and an activation- and coagulation-associated platelet proteomic signature. Tissue factor was selectively enriched in BxPC-3 EVs and detected in educated platelets. These findings identify EV cargo composition and donor lineage as determinants of platelet education and show that platelet adhesion and procoagulant activation are separable responses. The signature may support PDAC biomarker development and molecular subtyping.
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Sanchez-Manas et al. (2026) studied this question.
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