Beta IV spectrin inhibits the metastatic growth of melanoma by suppressing VEGFR2-driven tumor angiogenesis

Background: Tumor-associated angiogenesis mediates the growth and metastasis of most solid cancers. Targeted therapies of the VEGF pathways can effectively block these processes but often fail to provide lasting benefits due to acquired resistance and complications. Results: Recently, we discovered β_IV-spectrin as a powerful regulator of angiogenesis and potential new target. We previously reported that β_IV-spectrin is dynamically expressed in endothelial cells (EC) to induce VEGFR2 protein turnover during development. Here, we explored how β_IV-spectrin influences the tumor vasculature using the murine B16 melanoma model and determined that loss of EC-specific β_IV-spectrin dramatically promotes tumor growth and metastasis. Intraperitoneally injected B16 cells formed larger tumors with increased tumor vessel density and greater propensity for metastatic spread particularly to the chest cavity and lung compared to control mice. These results support β_IV-spectrin as a key regulator of tumor angiogenesis and a viable vascular target in cancer.