Epithelioid Hemangioendothelioma as a Model of YAP/TAZ-Driven Cancer: Insights from a Rare Fusion Sarcoma

Abstract

Epithelioid hemangioendothelioma (EHE) is a rare soft-tissue sarcoma involving cells with histologic markers that suggest an endothelial origin. Around 90% of EHEs are caused by the fusion of Transcriptional Co-activator with a PDZ-motif (TAZ) with Calmodulin Binding Transcription Activator 1 (CAMTA1), a central nervous system-specific transcription activator. The 10% of EHEs that lack the TAZ–CAMTA1 fusion instead have a fusion of Yes-associated Protein (YAP) and Transcription Factor E3 (TFE3) genes (YAP-TFE3). YAP and TAZ are well-defined downstream effectors in the Hippo pathway that promote cell growth when translocated to the nucleus. The TAZ–CAMTA1 fusion transcript is insensitive to the Hippo inhibitory signals that normally prevent this process and thus constitutively activates the TAZ transcriptome. In EHE, this causes tumors to form in a variety of organs and tissue types, most commonly the liver, lung, and bone. Its clinical course is unpredictable and highly variable. TAZ activation is known to contribute to key aspects of the cancer phenotype, including metastasis and fibrosis, and increased expression of TAZ is thought to be causally related to the progression of many cancers, including breast, lung, and liver. Therefore, understanding TAZ biology and the molecular mechanisms by which it promotes unregulated cell proliferation will yield insights and possibly improved treatments for both EHE as well as much more common cancers.

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

“…Here, YAP or TAZ are activated by gene rearrangements with either the transcription factor TFE3 (YAP-TFE3) or the calmodulin-binding transcription activator CAMTA1 (TAZ-CAMTA1) and retaining the YAP/TAZ TEAD-binding and WW domains [229][230][231]. Although the fusion protein can still be phosphorylated by LATS, the presence of a nuclear localization domain in the fusion partner suffices to keep the protein in the nucleus and constitutively activate the YAP/TAZ transcriptome [232].…”

<p>Metastatic Hepatic Epithelioid Hemangioendothelioma Treated with Olaratumab: A Falling Star Rising?</p>

“…37 Both fusion genes consist of the N-terminus of WWTR1 and YAP1, containing the WW (tryptophan-tryptophan) domain and TEAD binding domain respectively, fused with the C-terminus of CAMTA1 and TFE3 transcription factors. 5 Targeting YAP and TAZ interaction with TEAD or inhibiting Hippo pathway is a potent systemic treatment for EHE. Clinical trials testing MEK inhibitor trametinib and anti-microtubular agent eribulin are still running.…”

“…Interestingly, Hippo pathway gains a pivotal role in the tumorigenesis of hEHE. 5,6 Treatment of hEHE is still surgical. For localized disease; hepatic transplantation is the treatment of choice.…”

Molecular characterization of hepatic epithelioid hemangioendothelioma reveals alterations in various genes involved in DNA repair, epigenetic regulation, signaling pathways, and cell cycle control

“…As one molecular founder event, EHE (at any site) display either a characteristic fusion transcript of yes‐associated protein and transcription factor E3 (TFE3), reported in ~10% of EHE, or a fusion transcript of CAMTA1 and WWTR1, respectively, in roughly 90% of EHE, suggesting a dysregulation of the Hippo pathway in the majority of EHE and as a potential cause of their development. Although being both diagnosed as epthelioid hemangioendothelioma‐depending on the fusion protein‐ EHE might display different morphology, clinical behavior, and outcome . Protein expression of CAMTA1 and WWTR1 fusion can now be detected by immunohistochemistry supporting to establish the correct histological diagnosis .…”

“…Although being both diagnosed as epthelioid hemangioendotheliomadepending on the fusion protein-EHE might display different morphology, 11 clinical behavior, and outcome. 12 Protein expression of CAMTA1 and WWTR1 fusion can now be detected by immunohistochemistry supporting to establish the correct histological diagnosis. 13 Therapeutic options are mainly limited to resection, transplantation, 14 or systemic chemotherapy.…”