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PIK3CA和CCM突变通过类癌机制为海绵状血管瘤供能
2021-04-30 15:50

美国宾夕法尼亚大学Mark L. Kahn、杜克大学Douglas A. Marchuk等研究人员合作发现,PIK3CA和CCM突变通过类癌机制为海绵状血管瘤供能。该研究于2021年4月28日在线发表于国际一流学术期刊《自然》。

研究人员表示,血管畸形被认为是导致血管生长失调的单基因疾病。脑海绵状畸形(CCM)是由于抑制MEKK3活性所需的内皮CCM蛋白复合物失活而引起的。环境因素解释了个体之间CCM自然病史的差异,但是为何单个CCM经常表现出突然的、快速的生长并最终导致中风或癫痫发作尚不清楚。

研究人员证明,CCM的增长需要PI3K-mTOR信号的增强和CCM功能的丧失。研究人员在大多数人CCM的相同细胞中鉴定了PIK3CA功能获得(GOF)和CCM功能丧失(LOF)体细胞突变。使用小鼠模型,研究人员发现CCM的生长在内皮细胞中既需要PI3K GOF,又需要CCM LOF,并且CCM LOF和下游MEKK3效应子转录因子KLF4的表达增加均会增加内皮细胞中的mTOR信号传导。与这些发现一致,mTORC1抑制剂雷帕霉素在小鼠模型中有效阻断了CCM的形成。

研究人员建立了一种类似于癌症的三击机制,在这种机制中,侵袭性血管畸形是由于丧失了抑制血管生长的“抑制基因”而产生的,而获得了刺激血管过度生长的“癌基因”。这些发现表明,临床批准的mTORC1抑制剂可用于治疗侵袭性CCM。

附:英文原文

Title: PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism

Author: Aileen A. Ren, Daniel A. Snellings, Yourong S. Su, Courtney C. Hong, Marco Castro, Alan T. Tang, Matthew R. Detter, Nicholas Hobson, Romuald Girard, Sharbel Romanos, Rhonda Lightle, Thomas Moore, Robert Shenkar, Christian Benavides, M. Makenzie Beaman, Helge Mueller-Fielitz, Mei Chen, Patricia Mericko, Jisheng Yang, Derek C. Sung, Michael T. Lawton, Michael Ruppert, Markus Schwaninger, Jakob Krbelin, Michael Potente, Issam A. Awad, Douglas A. Marchuk, Mark L. Kahn

Issue&Volume: 2021-04-28

Abstract: Vascular malformations are considered monogenic disorders that result in dysregulated vessel growth. Cerebral cavernous malformations (CCMs) arise owing to inactivation of the endothelial CCM protein complex required to dampen MEKK3 activity1–4. Environmental factors explain differences in CCM natural history between individuals5, 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 signalling 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 signalling 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.

DOI: 10.1038/s41586-021-03562-8

Source: https://www.nature.com/articles/s41586-021-03562-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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