<scp>YAP1</scp> :: <scp>TFE3</scp> mediates endothelial‐to‐mesenchymal plasticity in epithelioid hemangioendothelioma

The rare vascular sarcoma epithelioid hemangioendothelioma (EHE) is defined by WWTR1 or YAP1 gene rearrangements that result in functional fusion proteins. Previous studies have demonstrated the ability of these gene fusions to function as constitutively active TEAD coactivators, while also retaining the ability to drive transcription of canonical CAMTA1 or TFE3 genes, respectively. To better understand the biology underlying EHE, we generated EHE in vitro models using endothelial cell lines and found that inducible expression of YAP1::TFE3 (YT) caused a significant change in cellular plasticity. Specifically, YT expression led to endothelial-to-mesenchymal transition (EndMT), a process in which endothelial cells lose their highly specialized identity and gain expression of genes typically associated with mesenchymal cells. This plasticity is associated with anoikis resistance and increased migratory phenotypes. Notably, YT drives this phenotypic change independent of TEAD activity but requires dimerization and DNA binding domains encoded by the C-terminal TFE3 gene. Overexpression of TFE3 is insufficient to fully recapitulate the EndMT phenotypes driven by YT; implying that, although dispensable for EndMT, YAP-TEAD activity provides a meaningful contribution. This work supports a growing body of evidence that YT and WWTR1-CAMTA1 driven EHE may have distinct biological mechanisms, underscoring a potentially targetable oncogenic molecular dependency.