Loss of CDKN2A Cooperates with WWTR1(TAZ)-CAMTA1 Gene Fusion to Promote Tumor Progression in Epithelioid Hemangioendothelioma

Purpose: Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma caused by the WWTR1(TAZ)-CAMTA1 (TC) gene fusion. This fusion gene has been observed in almost all reported EHE cases and functions as a constitutively activated TAZ. Sequencing of human tumors has, however, identified additional secondary mutations in approximately 50% of EHE, most commonly the loss of tumor suppressor CDKN2A. In this study, the effect of loss of CDKN2A in EHE tumorigenesis was evaluated.Experimental Design: Mice bearing a conditional TC allele were paired with a conditional Cdkn2a knockout allele and an endothe-lial-specific Cre. Histologic characterization and single-cell RNA-seq of the resultant tumors were performed. EHE cell lines were established through ex vivo culture of tumor cells and evaluated for sensitivity to TEAD inhibition and trametinib.Results: Loss of Cdkn2a within EHE was associated with more aggressive disease, as displayed by earlier tumor-related morbidity/ mortality and enhanced tumor cell proliferation. As no previous EHE cell lines exist, we attempted, successfully, to expand EHE tumor cells ex vivo and produced the first EHE cell lines. These cell lines are addicted to the TC oncoprotein, replicate the EHE transcriptional profile, and generate EHE tumors when injected into immunodeficient mice.Conclusions: CDKN2A loss enhances the tumorigenicity of EHE in vivo and enabled the generation of the first cell lines of this disease. These cell lines replicate key facets of the human disease phenotype. Therefore, these cell lines and allograft tumors gener-ated after implantation serve as robust model systems for thera-peutic testing of compounds directed at either EHE or other TAZ-driven cancers.

Automated summary

This study evaluated the effect of CDKN2A loss on EHE tumorigenesis. The loss of CDKN2A enhanced the invasiveness of EHE, leading to earlier tumor-related morbidity/mortality and increased tumor cell proliferation. Additionally, the study successfully established the first EHE cell lines, which replicated the transcriptional profile of EHE and generated EHE tumors in immunodeficient mice.