PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism.
PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism.
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PIK3CA和CCM突变通过癌症样机制促进海绵状瘤。
DOI：
10.1038/s41586-021-03562-8
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发表时间：
2021-06
期刊：
影响因子：
64.8
通讯作者：
Kahn ML
中科院分区：
文献类型：
--
作者：
Ren AA;Snellings DA;Su YS;Hong CC;Castro M;Tang AT;Detter MR;Hobson N;Girard R;Romanos S;Lightle R;Moore T;Shenkar R;Benavides C;Beaman MM;Müller-Fielitz H;Chen M;Mericko P;Yang J;Sung DC;Lawton MT;Ruppert JM;Schwaninger M;Körbelin J;Potente M;Awad IA;Marchuk DA;Kahn ML
血管畸形被认为是导致血管生长失调的单基因疾病。脑海绵状血管畸形（CCM）的出现是由于抑制MEKK 3活性所需的内皮CCM蛋白复合物失活。环境因素解释了个体之间CCM自然史的差异，但为什么单个CCM经常表现出突然、快速的生长，最终导致中风或癫痫发作尚不清楚。在这里，我们证明了CCM生长需要增加PI 3 K-mTOR信号传导和CCM功能的丧失。我们在大多数人CCM的相同细胞中鉴定了PIK 3CA功能获得（GOF）和CCM功能丧失（LOF）体细胞突变。使用小鼠模型，我们表明CCM生长需要内皮细胞中的PI 3 K GOF和CCM LOF两者，并且CCM LOF和转录因子KLF 4（下游MEKK 3效应物）的表达增加都增强内皮细胞中的mTOR信号传导。与这些发现一致，mTORC 1抑制剂雷帕霉素有效地阻断了小鼠模型中CCM的形成。我们建立了一个类似于癌症的三击机制，其中侵袭性血管畸形是通过限制血管生长的血管“抑制基因”的丢失和刺激过度血管生长的血管“癌基因”的获得而产生的。这些发现表明，侵袭性CCM可以使用临床批准的mTORC 1抑制剂进行治疗。
Vascular malformations are considered monogenic disorders that result in dysregulated vessel growth. Cerebral cavernous malformations (CCMs) arise due to inactivation of the endothelial CCM protein complex required to dampen MEKK3 activity. Environmental factors explain differences in CCM natural history between individuals, but why single CCMs often exhibit sudden, rapid growth culminating in stroke or seizure is unknown. Here we demonstrate that CCM growth requires increased PI3K-mTOR signaling and loss of CCM function. We identify PIK3CA gain of function (GOF) and CCM loss of function (LOF) somatic mutations in the same cells in a majority of human CCMs. Using mouse models, we show that CCM growth requires both PI3K GOF and CCM LOF in endothelial cells, and that both CCM LOF and increased expression of the transcription factor KLF4, a downstream MEKK3 effector, augment mTOR signaling in endothelial cells. Consistent with these findings, the mTORC1 inhibitor Rapamycin effectively blocks CCM formation 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 may be treated using clinically approved mTORC1 inhibitors.
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影响因子：
1.8
作者：
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