biostudies-literatureNeil ERCUK | MRC | Medical Research FoundationRCUK | Biotechnology and Biological Sciences Research CouncilEHE Rare Cancer Charity UK, PhD fellowship to Emily NeilBiotechnology and Biological Sciences Research Council1174https://www.ebi.ac.uk/biostudies/studies/S-EPMC10657451biostudies-literatureUnknown6(1)TAZ::CAMTA1 is a fusion protein found in over 90% of Epithelioid Hemangioendothelioma (EHE), a rare vascular sarcoma with an unpredictable disease course. To date, how TAZ::CAMTA1 initiates tumour formation remains unexplained. To study the oncogenic mechanism leading to EHE initiation, we developed a model system whereby TAZ::CAMTA1 expression is induced by doxycycline in primary endothelial cells. Using this model, we establish that upon TAZ::CAMTA1 expression endothelial cells rapidly enter a hypertranscription state, triggering considerable DNA damage. As a result, TC-expressing cells become trapped in S phase. Additionally, TAZ::CAMTA1-expressing endothelial cells have impaired homologous recombination, as shown by reduced BRCA1 and RAD51 foci formation. Consequently, the DNA damage remains unrepaired and TAZ::CAMTA1-expressing cells enter senescence. Knockout of Cdkn2a, the most common secondary mutation found in EHE, allows senescence bypass and uncontrolled growth. Together, this provides a mechanistic explanation for the clinical course of EHE and offers novel insight into therapeutic options.Communications biologyThe oncogenic fusion protein TAZ::CAMTA1 promotes genomic instability and senescence through hypertranscription.PMC10657451BB/R007209/1MR/P000673/1MR/T000384/1Pooley ONeil EParedes RKouskoff VRubin BfalseThe oncogenic fusion protein TAZ::CAMTA1 promotes genomic instability and senescence through hypertranscription.TAZ::CAMTA1 is a fusion protein found in over 90% of Epithelioid Hemangioendothelioma (EHE), a rare vascular sarcoma with an unpredictable disease course. To date, how TAZ::CAMTA1 initiates tumour formation remains unexplained. To study the oncogenic mechanism leading to EHE initiation, we developed a model system whereby TAZ::CAMTA1 expression is induced by doxycycline in primary endothelial cells. Using this model, we establish that upon TAZ::CAMTA1 expression endothelial cells rapidly enter a hypertranscription state, triggering considerable DNA damage. As a result, TC-expressing cells become trapped in S phase. Additionally, TAZ::CAMTA1-expressing endothelial cells have impaired homologous recombination, as shown by reduced BRCA1 and RAD51 foci formation. Consequently, the DNA damage remains unrepaired and TAZ::CAMTA1-expressing cells enter senescence. Knockout of Cdkn2a, the most common secondary mutation found in EHE, allows senescence bypass and uncontrolled growth. Together, this provides a mechanistic explanation for the clinical course of EHE and offers novel insight into therapeutic options.2023-01-01T00:00:00Z2023 Nov2025-04-18T13:13:14.258Z2025-02-19T01:52:17.8ZS-EPMC106574513798039010.1038/s42003-023-05540-4