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.

Keywords: TAZ–CAMTA1; YAP/TAZ; epithelioid hemangioendothelioma; hippo pathway; sarcoma.

Figure 1

Schematic of the Hippo pathway. The top left represents the activation of the Hippo pathway with phosphorylated core Hippo kinases and YAP/TAZ. Phosphorylated YAP/TAZ leads to cytoplasmic retention via binding to 14-3-3 proteins and/or polyubiquitination and proteolytic degradation. Upon Hippo inactivation (top right), YAP/TAZ can migrate to the nucleus, where it can bind to its TEAD cofactors and activate transcription.

Figure 2

Schematic of the proteins present in TAZ–CAMTA1 and YAP–TFE3 fusions, with the most common breakpoints within the proteins. TAZ and YAP are labeled above with the LATS1/2 phosphorylation sites. The markers below display the amino acid contributions of each exon, and the lines between sequences denote common fusion sites: WW: WW domain; TAD: transactivation domain; PDZ: PDZ-binding motif; CG-1: CG-1 DNA-binding domain; TIG: transcription-factor immunoglobulin domain; Ankyrin: ankyrin repeats; IQ: IQ calmodulin-binding motifs; NLS: nuclear-localization signal; SH3 BD: SH3-binding domain; bHLH: basic helix–loop–helix domain; LZ: leucine-zipper domain.

Figure 3

Strategies for targeting the oncogenic effects of TAZ–CAMTA1. Top left demonstrates the normal oncogenic effect of TC. Strategy A demonstrates inhibition of TC via increasing the action of negative regulators leading to cytoplasmic retention and degradation. Strategy B demonstrates inhibition by protein–protein interaction to disrupt the interaction between TC and TEAD proteins. Strategy C demonstrates inhibition of the downstream targets of TC/TEAD transcription, which promote oncogenesis.