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

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.

A Liver-Derived Vascular Lesion: Hepatic Hemangioma or Hepatic Epithelioid Hemangioendothelioma?

“…41.7 years is known to be the median affected age, and female-to-male predominance is estimated to be 3:2. 3 The clinical manifestations are not specified for hepatic EHE. The usual symptoms are right upper quadrant pain (48.6%), hepatomegaly (20.4%), constitutional syndrome with progressive liver damage, and weight loss (15.6%).…”

“…The usual symptoms are right upper quadrant pain (48.6%), hepatomegaly (20.4%), constitutional syndrome with progressive liver damage, and weight loss (15.6%). 3 Infrequent symptoms include Budd-Chiari syndrome or liver failure. Laboratory findings may indicate abnormal liver function.…”

“…1,2 Hepatic EHE is a low-to-moderategrade tumor associated with an intermediate malignant potential between hemangioma and hemangiosarcoma. 3 Various non-specific clinical manifestations are expected. The usual symptoms included right upper quadrant pain (48.6%), hepatomegaly (20.4%), and weight loss.…”

Nuclear Import and Export of YAP and TAZ

“…(3) The presence of various YAP or TAZ fusion proteins is the direct cause for tumor formation in a set of rare malignances, exemplified by epithelioid hemangioendothelioma [56][57][58]. The resulting oncoproteins are composed of an N-terminal portion of YAP or TAZ fused to a C-terminal sequence of another protein (e.g., TAZ-CAMTA1, YAP-TFE3); they are resistant to upstream regulatory signals and constantly nuclear, as dictated by the fusion partner.…”

Identification of a Gene Signature That Predicts Dependence upon YAP/TAZ-TEAD

“…However, as is the case for most targeted therapies, the success of these treatments will depend upon whether tumors that are dependent upon YAP/TAZ-TEAD can be distinguished from those that are not. This will be straightforward for cancers driven by mutations known to cause YAP or TAZ activation, such as NF2-mutant mesothelioma [ 22 ], GNAQ-mutant uveal melanoma [ 23 ], Epithelioid Hemangioendothelioma (EHE) (which is driven by the oncogenic TAZ-CAMTA1 fusion protein [ 24 , 25 , 26 ]), and other cancers driven by YAP fusions [ 27 ]. However, in most of the cancers where YAP and TAZ play causal roles, mutations or alterations in the Hippo Pathway or YAP and TAZ themselves are rare, so biomarkers that can predict sensitivity to YAP/TAZ-TEAD inhibition will be essential.…”