Aberrant VEGFR2 supports tumor growth by extracellular matrix remodeling

The extracellular matrix shapes tumor architecture, cell behavior and therapy response. Here, we identify aberrant activation of the receptor tyrosine kinase VEGFR2 as a driver of tumor-promoting ECM remodeling in melanoma and ovarian cancer. ECM alterations in terms of composition and organization were observed in Sk-Mel-31 melanoma xenografts expressing the oncogenic VEGFR2^R1032Q and in ovarian tumors with VEGFR2 hyperactivation. Down-modulation of VEGFR2 normalized ECM architecture. Decellularized ECM from VEGFR2^R1032Q melanoma cells directly modified the behavior of VEGFR2^WT tumor cells, increasing monolayer fluidity and mitochondrial activation. Transcriptomic profiling revealed a dysregulation of genes involved in ECM structure and remodeling, mediated by the PI3K-AKT and ERK pathways. Pharmacological inhibition of VEGFR2 with tyrosine kinase inhibitors, such as lenvatinib, partially reverted ECM alterations in vitro and in vivo, reducing matrix deposition and modifying its organization. These data identify VEGFR2 as a regulator of tumor ECM dynamics and suggest that its inhibition may restore ECM organization, offering a therapeutic strategy to reprogram the tumor microenvironment and limit cancer progression.