Endothelial Fat4 regulates tumor angiogenesis and tumor immunity 9173

Abstract Description Tumor angiogenesis plays a crucial role in cancer progression and is linked to the regulation of immune cell migration. Vascular endothelial growth factor A (VEGF-A) is a well-known angiogenic factor and has been used as the target of anti-angiogenic drugs. However, targeting the VEGF signaling pathway provides limited therapeutic efficacy and unexpected side effects. Therefore, new targets are needed to develop anti-angiogenic therapies. We previously identified an inverse correlation between tumor angiogenesis and tumor immunity and found that cancer patients with low angiogenesis and high T cell immunity responded best to immune checkpoint blockade therapy. Notably, patients exhibiting low angiogenesis and high T cell immunity showed elevated Fat atypical cadherin 4 (FAT4) mutations. In this study, we investigated whether Fat4 could serve as a novel target and regulate tumor angiogenesis. We discovered a positive correlation between angiogenic scores and FAT4 expression in cancer patients. Fat4 expression was mainly observed in tumor endothelial cells, and Fat4 deficiency resulted in defects in sprouting, tube formation, and motility of endothelial cells (ECs). EC-specific Fat4 knockout mice showed reduced tumor angiogenesis and tumor growth. Importantly, impaired tumor angiogenesis created an anti-tumor microenvironment in Fat4 knockout mice. Overall, these findings suggest that inhibiting proangiogenic Fat4 diminishes tumor angiogenesis and enhances anti-tumor immunity. Funding Sources Supported by NRF RS-2024-00412492. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)