Oncogenic VEGFR2 rewires the extracellular matrix to impair endothelial mechanics and destabilize tumor vasculature.

Solid tumors are highly dynamic environments, in which endothelial cells (ECs) interface with blood, cancer cells, and the extracellular matrix (ECM), thereby regulating tumor behavior and metastatic dissemination. We recently showed that aberrant Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) activation promotes tumor progression through ECM remodeling. Here we investigated whether VEGFR2-driven ECM remodeling affects EC behavior and vessel stability. Using decellularized ECM from Sk-Mel-31 melanoma cells expressing either VEGFR2WT or the aberrant VEGFR2R1032Q mutant, we found that VEGFR2R1032Q reshapes ECM composition, including core matrisome components, ECM-modifying enzymes, and vascular-associated proteins. ECs seeded on VEGFR2R1032Q-derived ECM displayed altered adhesion dynamics, characterized by focal adhesion remodeling, increased haptotaxis, and impaired morphogenic capacity. This remodeled ECM also induced cytoskeletal reorganization, disruption of VE-cadherin junctions via RhoA activation. Consistently, VEGFR2R1032Q-derived tumors exhibited more immature vessels with discontinuous junctions and the expression of mesenchymal markers. Under laminar flow, ECs exposed to VEGFR2R1032Q-ECM showed a delayed calcium dynamic and Yap localization, defective polarization, actin alignment, and impaired shear-stress adaptation. Overall, these findings identify VEGFR2-driven ECM remodeling as a non-cell-autonomous mechanism that destabilizes tumor vasculature by impairing endothelial adhesion, mechanosensing, and junctional integrity, highlighting tumor/ECM/endothelium crosstalk as a potential therapeutic vulnerability.