Abstract:
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.
摘要:
TAZ::CAMTA1是在超过90%的上皮样血管内皮瘤(EHE)中发现的融合蛋白,罕见的血管肉瘤,病程不可预测。迄今为止,TAZ::CAMTA1如何引发肿瘤形成仍无法解释。为了研究导致EHE启动的致癌机制,我们开发了一个模型系统,利用多西环素在原代内皮细胞中诱导TAZ::CAMTA1表达.使用这个模型,我们确定,在TAZ::CAMTA1表达后,内皮细胞迅速进入超转录状态,引发相当大的DNA损伤.因此,表达TC的细胞陷入S期。此外,TAZ:表达CAMTA1的内皮细胞同源重组受损,如减少BRCA1和RAD51病灶形成所示。因此,DNA损伤仍未修复,表达TAZ::CAMTA1的细胞进入衰老。敲除Cdkn2a,EHE中最常见的次级突变,允许绕过衰老和不受控制的生长。一起,这为EHE的临床病程提供了机制上的解释,并为治疗方案提供了新的见解.