Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Genes Dev. 2021 Apr 1;35(7-8):512-527. doi: 10.1101/gad.348220.120. Epub 2021 Mar 25.
Epithelioid hemangioendothelioma (EHE) is a genetically homogenous vascular sarcoma that is a paradigm for TAZ dysregulation in cancer. EHE harbors a (TAZ)- gene fusion in >90% of cases, 45% of which have no other genetic alterations. In this study, we used a first of its kind approach to target the gene fusion to the locus, to develop a conditional EHE mouse model whereby is controlled by the endogenous transcriptional regulators upon Cre activation. These mice develop EHE tumors that are indistinguishable from human EHE clinically, histologically, immunohistochemically, and genetically. Overall, these results demonstrate unequivocally that TAZ-CAMTA1 is sufficient to drive EHE formation with exquisite specificity, as no other tumor types were observed. Furthermore, we fully credential this unique EHE mouse model as a valid preclinical model for understanding the role of TAZ dysregulation in cancer formation and for testing therapies directed at TAZ-CAMTA1, TAZ, and YAP/TAZ signaling.
上皮样血管内皮细胞瘤 (EHE) 是一种基因同质的血管肉瘤，是癌症中 TAZ 失调的典范。EHE 在超过 90%的病例中存在 (TAZ)-基因融合，其中 45%没有其他遗传改变。在这项研究中，我们使用了一种首创的方法将 基因融合靶向到 基因座，以开发一种条件性 EHE 小鼠模型，其中在 Cre 激活时， 受内源性转录调节剂控制。这些小鼠发展出的 EHE 肿瘤在临床上、组织学上、免疫组织化学上和遗传上与人类 EHE 无法区分。总的来说，这些结果明确表明，TAZ-CAMTA1 足以驱动 EHE 的形成，具有极高的特异性，因为没有观察到其他肿瘤类型。此外，我们充分证明了这种独特的 EHE 小鼠模型是一个有效的临床前模型，可用于了解 TAZ 失调在癌症形成中的作用，以及测试针对 TAZ-CAMTA1、TAZ 和 YAP/TAZ 信号的治疗方法。
