Abstract
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 VEGFR2R1032Q and in ovarian tumors with VEGFR2 hyperactivation. Down-modulation of VEGFR2 normalized ECM architecture. Decellularized ECM from VEGFR2R1032Q melanoma cells directly modified the behavior of VEGFR2WT 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.
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Acknowledgements
This work was funded by Associazione Italiana Ricerca sul Cancro AIRC (AIRC grant IG17276 to SM); AIRC fellowship for Italy (grant n° 26917 to MC); PNRR - CN3 “Sviluppo di Terapia Genica e Farmaci con Tecnologia ad RNA” PNRR M4C2-Investimento 1.4-CN00000041 finanziato dall’Unione Europea–NextGenerationEU”(to AV, MS, and MC); Cariplo Foundation to EG. Research funds from University of Brescia (ex 60%) 2024 to SM and MC, and “5 per mille” to MC; from MIUR to Consorzio Interuniversitario di Biotecnologie (CIB) to CR, EG, MC and SM. Funding bodies did not have any role in designing the study, collecting, analyzing, and interpreting data or in writing the manuscript. The authors performed experiments at the Imaging Platform and the Animal facility of the Department and Animal of Translational and Molecular Medicine of the University of Brescia.
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MC, CR, EG, AV, MD, CM,CP, CR, EM, and MT designed and performed the experiments. MC and SM conceived, planned the experiments, and wrote the manuscript. SM supervised the work and reviewed the manuscript. All authors discussed the results and contributed to the final manuscript.
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Corsini, M., Ravelli, C., Domenichini, M. et al. Aberrant VEGFR2 supports tumor growth by extracellular matrix remodeling. Cell Death Dis (2026). https://doi.org/10.1038/s41419-025-08404-3
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DOI: https://doi.org/10.1038/s41419-025-08404-3
