PO01 | MELANOMA-DERIVED EXTRACELLULAR VESICLES DRIVE VON WILLEBRAND FACTOR–DEPENDENT THROMBOSIS AND METASTASIS

Y. Wang^1|2, X. Liu¹, T. Downar³, A. Topuz⁴, A. Bauer¹, J. Kött^1|5, K. Nekipelov⁶, S. Brenna⁷, G. Bendas⁶, B. Puig⁷, S. Schneider¹, D. Fedosov⁴, C. Gorzelanny¹ | ¹Department of Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; ²Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; ³Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; ⁴Institute for Advanced Simulation (IAS-2), Forschungszentrum Jülich, Jülich, Germany; ⁵Fleur Hiege Center for Skin Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; ⁶Pharmaceutical Institute, University of Bonn, Bonn, Germany; ⁷Neurology Department, Experimental Research in Stroke and Inflammation (ERSI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Cancer-associated thrombosis (CAT) is a major complication of malignancy and is closely linked to tumor progression and metastasis. Extracellular vesicles (EVs) derived from tumors, especially those that express tissue factor (TF), have been associated with procoagulant activity. However, the precise mechanisms by which circulating EVs interact with the vascular hemostatic system remain inadequately elucidated. In this study, we investigated whether melanoma-derived EVs promote thrombosis through interactions with von Willebrand factor (vWF) under flow conditions. Using microfluidic assays that mimic a tumor-activated vascular environment, we demonstrate that shear-activated vWF functions as a size-selective molecular filter that preferentially captures objects smaller than ~4 μm, including platelets and tumor-derived EVs, while excluding larger cells. Although intact tumor cells do not directly bind vWF under physiological flow, the coordinated binding of EVs and platelets to extended vWF promotes platelet aggregation and the formation of platelet-rich microthrombi under flow, leading to the entrapment of circulating tumor cells within thrombi and fostering metastatic dissemination. These findings reveal a previously unrecognized mechanism by which melanoma-derived EVs couple endothelial activation, thrombosis, and metastatic dissemination via vWF-dependent interactions. Targeting ULvWF formation or EV–vWF binding may therefore represent a novel strategy to reduce cancer-associated thrombosis and limit metastatic progression.