Abstract 2851: YAP1-TFE3 fusion protein promotes EndMT in epithelioid hemangioendothelioma

Abstract Epithelioid Hemangioendothelioma (EHE) is an ultra-rare vascular cancer driven by chromosomal translocations resulting in the TAZ-CAMTA1 or YAP1-TFE3 fusion transcription factors. Despite some knowledge of the disease defining fusion proteins, the mechanisms driving tumorigenesis remain largely unclear. To study the effects of EHE fusion protein expression on the biology of endothelial cells, we generated EHE cell models using the murine endothelial cell line MS-1 and the human endothelial cell line HUVEC. Expression of TC and YT led to increased Hippo target gene expression, as expected. However, we observed a striking phenotype in YT-expressing endothelial cells associated with morphologic changes, enhanced migratory potential, and anchorage independence growth. These phenotypic changes are consistent with a process known as endothelial-to-mesenchymal transition (EndMT). EndMT is a physiological process where endothelial cells lose their endothelial identity and become more mesenchymal-like. Indeed, we observe transcriptional changes consistent with EndMT such as the reduction in expression of multiple endothelial-specific markers and a significant increase in transcription of mesenchymal marker, Acta2. We utilize several gain- and loss-of-function approaches to further investigate the mechanisms and impact of EndMT in tumorigenesis. Citation Format: Ant Murphy, Sam Hartzler, Paula Carranza, Madison Yates, Nimod Janson, Shyaman Jayasundara, Majid Kazemian, Jason A. Hanna. YAP1-TFE3 fusion protein promotes EndMT in epithelioid hemangioendothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2851.