Translating molecular mechanisms of epithelioid hemangioendothelioma to improve patient outcome

Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma of vascular origin composed of epithelioid endothelial cells within myxohyaline stroma. Molecularly, it is characterized in over 90 % of cases by a fusion between WW domain-containing transcription regulator 1 (WWTR1-TAZ) and calmodulin-binding transcription activator 1 (CAMTA1), or, in approximately 5 % of cases, by a yes-associated protein 1 (YAP1) and transcription factor E3 (TFE3) fusion. Clinically, EHE is remarkably heterogeneous, ranging from unifocal or multifocal lesions confined to a single organ to disseminated, multi-organ involvement indicative of systemic disease. EHE-specific treatments are lacking and anthracyclines, the first-line treatment for sarcomas, are rarely effective. Tumor models with the TAZ::CAMTA1 translocation have led to advance understanding of how YAP/TAZ-fusion oncoproteins drive EHE tumorigenesis, through the interaction with TEA domain 1-4 (TEAD1-4) transcription factors, which ultimately alters transcriptional activity. To strengthen the translational relevance of these findings, patient-derived models were established to complement insights gained from murine EHE models and cell lines engineered with the translocations. Among perturbated pathways, mTOR and MEK/ERK determine EHE progression and have been recently targeted in clinical studies, showing effect on tumor progression and EHE-related symptoms. These pathways also influence the tumor release of circulating cytokines, such as GDF-15 which is associated to patient outcomes. In this review we summarize advancements in the understanding of EHE biology that are closely associated with the EHE-specific translocations together with their implication for mechanisms that underpin EHE aggressiveness, with the final aim of highlighting EHE-related biomarkers and innovative therapeutic strategies.