WWTR1(TAZ)-CAMTA1 reprograms endothelial cells to drive epithelioid hemangioendothelioma.

Abstract

Epithelioid hemangioendothelioma (EHE) is a poorly understood and devastating vascular cancer. Sequencing of EHE has revealed a unique gene fusion between the Hippo pathway nuclear effector TAZ (WWTR1) and the brain-enriched transcription factor CAMTA1 in ∼90% of cases. However, it remains unclear whether the TAZ-CAMTA1 gene fusion is a driver of EHE, and potential targeted therapies are unknown. Here, we show that TAZ-CAMTA1 expression in endothelial cells is sufficient to drive the formation of vascular tumors with the distinctive features of EHE, and inhibition of TAZ-CAMTA1 results in the regression of these vascular tumors. We further show that activated TAZ resembles TAZ-CAMTA1 in driving the formation of EHE-like vascular tumors, suggesting that constitutive activation of TAZ underlies the pathological features of EHE. We show that TAZ-CAMTA1 initiates an angiogenic and regenerative-like transcriptional program in endothelial cells, and disruption of the TAZ-CAMTA1-TEAD interaction or ectopic expression of a dominant negative TEAD in vivo inhibits TAZ-CAMTA1-mediated transformation. Our study provides the first genetic model of a TAZ fusion oncoprotein driving its associated human cancer, pinpointing TAZ-CAMTA1 as the key driver and a valid therapeutic target of EHE.

• Authors: Jordan H Driskill, Yonggang Zheng, Bo-Kuan Wu, Li Wang, Jing Cai, Dinesh Rakheja, Michael Dellinger, Duojia Pan
• Journal: Genes & development (Genes Dev) Vol. 35 Issue 7-8 Pg. 495-511 (04 01 2021) ISSN: 1549-5477 [Electronic] United States
• PMID: 33766984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Driskill et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• CAMTA1 protein, human
• Calcium-Binding Proteins
• Intracellular Signaling Peptides and Proteins
• Trans-Activators
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• WWTR1 protein, human

Topics

• Animals
• Calcium-Binding Proteins (genetics, metabolism)
• Carcinogenesis (genetics)
• Cell Line, Tumor
• Endothelial Cells (pathology)
• Gene Expression Regulation, Neoplastic
• Gene Fusion
• Hemangioendothelioma, Epithelioid (genetics, pathology)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Mice
• Trans-Activators (genetics, metabolism)
• Transcriptional Coactivator with PDZ-Binding Motif Proteins