OC13 | VON WILLEBRAND FACTOR PREDICTS POOR OUTCOME IN PANCREATIC CANCER AND MEDIATES TUMOR-ENDOTHELIUM INTERACTIONS FACILITATING METASTASIS

B. Ünlü¹, Z. Zhao¹, N. Joshi¹, S. De¹, A. Chion¹, I. Schoen¹, J. O’Donnell¹, M. Flick², M. Fishel^3|4, J. O’Sullivan¹ | ¹School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland; ²UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, USA; ³IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA; ⁴Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

Introduction. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by chemotherapy resistance, early metastatic spread, and a strong prothrombotic phenotype. Previously, we reported that breast cancer cells induce endothelial cell (EC) activation and rapid von Willebrand Factor (VWF) release, thereby promoting tumor progression. We want to investigate the mechanistic role of VWF in driving PDAC metastasis. Elevated VWF levels have been associated with increased thrombotic risk and metastatic disease, and yet its role in PDAC remains poorly defined.

Aim. The goal is to elucidate the pro-tumorigenic role of VWF in PDAC progression and metastatic dissemination.

Materials and Methods. Plasma VWF antigen (VWF:Ag) levels were measured in treatment-naïve PDAC patients and correlated with survival. Interactions between VWF and PDAC cell lines (PANC1, BxPC3) were assessed by flow cytometry, immunofluorescence, and microfluidic endothelial adhesion assays. VWF-induced signaling was examined using qPCR, proliferation, migration, and invasion assays.
Results. PDAC patients exhibited 2.5-fold higher plasma VWF:Ag levels than healthy controls (253±147 vs 106±25 IU/dL, p<0.001), which is associated with reduced survival. Crosstalk between tumor cells and ECs was evident as conditioned media from PANC1 and BxPC3 cells induced a 4-fold increase in VWF secretion from ECs. This activation was facilitated by VEGF-A expressed in BxPC3, but was independent of VEGF-A in PANC1. To unravel the role of VWF in metastasis under static and venous flow conditions. Under static tube-based binding conditions, PANC1 adhered to VWF, while BxPC3 showed minimal binding. Caplacizumab, a nanobody that targets the VWF A1-domain, cut PANC1-VWF binding by 52%. This suggests that the A1 domain plays a role in PDAC adhesion. Under venous flow conditions, anti-VWF treatment markedly reduced PANC1 adhesion to activated ECs (38.1±23.5 vs. 7.7±6.0 cells/mm², p<0.01). In contrast, BxPC3 adhesion was VWF-independent but required integrin-mediated interactions. Furthermore, treatment of PANC1 with 50 nM VWF significantly increased proliferation (1.25-fold), migration (2.4-fold) and invasion (2.3-fold).

Conclusions. Elevated plasma VWF levels associated with poor survival in PDAC. VWF may contribute to metastatic dissemination via tumor cells' capture under flow and supporting invasive tumor cell behavior. This highlights VWF as a potential therapeutic target in PDAC.