Unraveling the Biology of Epithelioid Hemangioendothelioma, a TAZ–CAMTA1 Fusion Driven Sarcoma

SIMPLE SUMMARY: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer that involves a gain-of-function gene fusion involving TAZ, a transcriptional coactivator, and one of two end effectors of the Hippo pathway. Although the activity of TAZ and/or YAP, a paralog of TAZ, is consistently altered in many cancers, genetic alterations involving YAP/TAZ are rare, and the precise mechanisms by which YAP/TAZ are activated are not well understood in most cancers. Because WWTR1(TAZ)–CAMTA1 is the only genetic alteration in approximately half of EHE, EHE is a genetically clean and homogenous system for understanding how the dysregulation of TAZ promotes tumorigenesis. Therefore, by using EHE as a model system, we hope to elucidate the essential biological pathways mediated by TAZ and identify mechanisms to target them. The findings of EHE research can be applied to other cancers that are addicted to high YAP/TAZ activity. ABSTRACT: The activities of YAP and TAZ, the end effectors of the Hippo pathway, are consistently altered in cancer, and this dysregulation drives aggressive tumor phenotypes. While the actions of these two proteins aid in tumorigenesis in the majority of cancers, the dysregulation of these proteins is rarely sufficient for initial tumor development. Herein, we present a unique TAZ-driven cancer, epithelioid hemangioendothelioma (EHE), which harbors a WWTR1(TAZ)–CAMTA1 gene fusion in at least 90% of cases. Recent investigations have elucidated the mechanisms by which YAP/TAP-fusion oncoproteins function and drive tumorigenesis. This review presents a critical evaluation of this recent work, with a particular focus on how the oncoproteins alter the normal activity of TAZ and YAP, and, concurrently, we generate a framework for how we can target the gene fusions in patients. Since EHE represents a paradigm of YAP/TAZ dysregulation in cancer, targeted therapies for EHE may also be effective against other YAP/TAZ-dependent cancers.