Abstract LB464: Identification of endothelial Ovol1 as a novel regulator of Slug-dependent angiogenic signaling in colorectal cancer

Cancer progression and metastasis depends upon tumor neovascularization to connect solid tumors to the systemic circulation. Endothelial cells that line the inner lumen of blood vessels critically support the pathological angiogenesis needed to form tumor blood vessels, and anti-angiogenics are frequently used as part of chemotherapy treatment for many cancer types. However, anti-angiogenics are often less effective than expected such as in colorectal cancer where the VEGF inhibitor bevacizumab improves outcomes in only a subset of patients. This suggests that new strategies targeting core angiogenic pathways may be more promising. We recently found that transcription factor Slug mediates a partial endothelial-to-mesenchymal transition (pEndoMT) in endothelial cells that is essential for sprouting angiogenesis and tumor neovascularization. However, an outstanding question remains: what regulates Slug during tumor angiogenesis? Sequence analysis of the Slug gene reveals two predicted DNA-binding sites for the transcription factor Ovol1. Here, we explore the hypothesis that Ovol1 regulates Slug to induce pEndoMT in angiogenesis. We show that Ovol1 is necessary and sufficient to drive angiogenesis in vitro in a Slug-dependent manner. Constitutive overexpression of Ovol1 increases Slug expression in cultured endothelial cells, and endothelial-specific Ovol1 knockout leads to suppression of colorectal cancer tumor xenograft growth in mice. In summary, we report that Ovol1 is a novel regulator of sprouting angiogenesis and tumor neovascularization via effects on Slug levels. This expanded understanding of Ovol-Slug regulation of the pEndoMT signaling axis in endothelial cells and in colorectal cancer is expected to help drive development of new and potentially more effective anti-angiogenic therapies that may one day help to better suppress tumor growth in cancer patients. (Funding: Louisiana Cancer Research Center New Investigator Award (CR1305A6), Louisiana Cancer Research Center Summer Undergraduate Cancer Research Experience Program, Tulane Carol Lavin Bernick Faculty Research Award, and Tulane Committee on Research Fellowship Award) Citation Format: Kapil Thapa, Brandon Burow, Emma Bates, Jennifer Fang. Identification of endothelial Ovol1 as a novel regulator of Slug-dependent angiogenic signaling in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB464.