Abstract LT007: YAP1::TFE3 fusion protein promotes transformation and EndMT plasticity in epithelioid hemangioendothelioma

Abstract Epithelioid Hemangioendothelioma (EHE) is a rare vascular sarcoma driven by chromosomal translocations resulting in the TAZ::CAMTA1 (TC) or YAP1::TFE3 (YT) fusion transcription factors. Despite some knowledge of the disease defining fusion proteins, the mechanisms underlying tumorigenesis remain largely unclear leading to a lack of targeted therapies to benefit patients. Since both EHE fusion proteins involve the TEAD coactivators TAZ/YAP, previous work has focused on Hippo pathway mechanisms. To study the effects of the EHE fusion proteins on the biology of endothelial cells, we generated doxycycline-inducible endothelial cell models using the murine MS-1 and the human HUVEC cell lines. Expression of TC and YT led to increased YAP/TAZ-TEAD target gene expression, as expected. However, we observed a striking phenotype in YT-expressing endothelial cells associated with morphologic changes, enhanced migratory potential, anchorage independence growth, and anoikis resistance. These phenotypic changes are consistent with a transition 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. Utilizing mutant versions of YT, we discovered that this phenotypic plasticity is independent of TEAD activity but requires dimerization and DNA binding domains encoded by the C-terminal TFE3 activity of YT. Furthermore, TFE3 dimerization disruption via repurposing the anti-histamine, terfenadine is able to partially reverse EndMT phenotypes. This work supports the histologic and clinical characteristics that YT and TC driven EHE may have distinct mechanisms and should be considered as distinct subtypes of EHE. This work highlights the potential efficacy of TFE3 directed therapies for YT-EHE tumors. Citation Format: Ant Murphy, Sam Hartzler, Paula Carranza, Bozhi Liu, Nimod Janson, Shyaman Jayasundara, Majid Kazemian, Jason A. Hanna. YAP1::TFE3 fusion protein promotes transformation and EndMT plasticity in epithelioid hemangioendothelioma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr LT007.