Defensin-Rich Platelets Drive Pro-Tumorigenic Programs in Pancreatic Adenocarcinoma

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies, driven by late diagnosis, limited therapeutic options, and high metastatic potential. Beyond their canonical roles in hemostasis, platelets have emerged as active modulators of tumor progression and promising noninvasive biomarkers. Among platelet-associated molecules, α-defensins, particularly Defensin Alpha 1/3 (<i>DEFA1/3</i>), have been implicated in inflammation and immunity; however, their contribution to PDAC pathogenesis remains unclear. We combined bioinformatic analysis of platelet transcriptomes with functional and in vivo zebrafish xenograft validation to investigate the impact of <i>DEFA1/3</i> on PDAC aggressiveness. <i>DEFA1/3</i> was significantly upregulated in PDAC-derived platelets. Defensin-enriched platelet-like particles (defensin-rich platelets, DRPs) and recombinant DEFA1/3 enhanced pancreatic cancer cell proliferation, migration, and three-dimensional growth in vitro and promoted tumor dissemination in zebrafish xenografts. Transcriptomic profiling revealed the upregulation of <i>SPARC</i>, <i>KDM6A</i>, and <i>GATA6</i>, whereas clinical data from The Cancer Genome Atlas (TCGA)-PDAC linked high <i>DEFA1/3</i> expression to poor survival, increased immune infiltration, and activation of epithelial-mesenchymal transition (EMT). Platelet-derived <i>DEFA1/3</i> acts as a functional modulator of PDAC progression, linking platelet granule content to tumor aggressiveness and highlighting a potential biomarker and therapeutic target within the platelet-tumor axis.