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

## TL;DR

This study shows that platelets containing defensins, specifically DEFA1/3, promote the growth and spread of pancreatic cancer, suggesting a new target for treatment.

## Contribution

The study identifies DEFA1/3 in platelets as a novel driver of pancreatic cancer progression and metastasis.

## Key findings

- DEFA1/3 is significantly upregulated in platelets derived from pancreatic cancer patients.
- Defensin-rich platelets enhance cancer cell proliferation and migration in vitro and in zebrafish models.
- High DEFA1/3 expression correlates with poor survival and EMT activation in pancreatic cancer patients.

## Abstract

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 (DEFA1/3), 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 DEFA1/3 on PDAC aggressiveness. DEFA1/3 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 SPARC, KDM6A, and GATA6, whereas clinical data from The Cancer Genome Atlas (TCGA)-PDAC linked high DEFA1/3 expression to poor survival, increased immune infiltration, and activation of epithelial–mesenchymal transition (EMT). Platelet-derived DEFA1/3 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.