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PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism
Nature ( IF 64.8 ) Pub Date : 2021-04-28 , DOI: 10.1038/s41586-021-03562-8
Aileen A Ren 1 , Daniel A Snellings 2 , Yourong S Su 3 , Courtney C Hong 1 , Marco Castro 4 , Alan T Tang 1 , Matthew R Detter 2 , Nicholas Hobson 5 , Romuald Girard 5 , Sharbel Romanos 5 , Rhonda Lightle 5 , Thomas Moore 5 , Robert Shenkar 5 , Christian Benavides 2 , M Makenzie Beaman 2 , Helge Müller-Fielitz 6 , Mei Chen 1 , Patricia Mericko 1 , Jisheng Yang 1 , Derek C Sung 1 , Michael T Lawton 7 , J Michael Ruppert 8 , Markus Schwaninger 6 , Jakob Körbelin 9 , Michael Potente 4, 10, 11 , Issam A Awad 5 , Douglas A Marchuk 2 , Mark L Kahn 1
Affiliation  

Vascular malformations are thought to be monogenic disorders that result in dysregulated growth of blood vessels. In the brain, cerebral cavernous malformations (CCMs) arise owing to inactivation of the endothelial CCM protein complex, which is required to dampen the activity of the kinase MEKK31,2,3,4. Environmental factors can explain differences in the natural history of CCMs between individuals5, but why single CCMs often exhibit sudden, rapid growth, culminating in strokes or seizures, is unknown. Here we show that growth of CCMs requires increased signalling through the phosphatidylinositol-3-kinase (PI3K)–mTOR pathway as well as loss of function of the CCM complex. We identify somatic gain-of-function mutations in PIK3CA and loss-of-function mutations in the CCM complex in the same cells in a majority of human CCMs. Using mouse models, we show that growth of CCMs requires both PI3K gain of function and CCM loss of function in endothelial cells, and that both CCM loss of function and increased expression of the transcription factor KLF4 (a downstream effector of MEKK3) augment mTOR signalling in endothelial cells. Consistent with these findings, the mTORC1 inhibitor rapamycin effectively blocks the formation of CCMs in mouse models. We establish a three-hit mechanism analogous to cancer, in which aggressive vascular malformations arise through the loss of vascular ‘suppressor genes’ that constrain vessel growth and gain of a vascular ‘oncogene’ that stimulates excess vessel growth. These findings suggest that aggressive CCMs could be treated using clinically approved mTORC1 inhibitors.



中文翻译:

PIK3CA 和 CCM 突变通过类似癌症的机制加剧海绵状血管瘤

血管畸形被认为是导致血管生长失调的单基因疾病。在大脑中,脑海绵状血管瘤 (CCM) 是由于内皮 CCM 蛋白复合物失活而引起的,而内皮 CCM 蛋白复合物是抑制激酶 MEKK3 1,2,3,4活性所必需的。环境因素可以解释个体之间 CCM 自然史的差异5,但为什么单个 CCM 经常表现出突然、快速生长,最终导致中风或癫痫发作,尚不清楚。在这里,我们表明,CCM 的生长需要通过磷脂酰肌醇-3-激酶 (PI3K)-mTOR 途径增加信号传导以及 CCM 复合物功能的丧失。我们在大多数人类 CCM 的相同细胞中鉴定出PIK3CA的体细胞功能获得突变和 CCM 复合体的功能丧失突变。使用小鼠模型,我们发现 CCM 的生长需要内皮细胞中 PI3K 功能的获得和 CCM 功能的丧失,并且 CCM 功能丧失和转录因子 KLF4(MEKK3 的下游效应子)表达增加都会增强 mTOR 信号传导在内皮细胞中。与这些发现一致的是,mTORC1 抑制剂雷帕霉素可有效阻止小鼠模型中 CCM 的形成。我们建立了一种类似于癌症的三击机制,其中侵袭性血管畸形是由于限制血管生长的血管“抑制基因”的丧失和刺激血管过度生长的血管“癌基因”的获得而引起的。这些发现表明侵袭性 CCM 可以使用临床批准的 mTORC1 抑制剂进行治疗。

更新日期:2021-04-28
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