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首页> 外文期刊>Nature >PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism
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PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism

机译：Pik3Ca和CCM突变通过癌症机制燃料飞艇

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摘要

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 MEKK3~(1-4). Environmental factors can explain differences in the natural history of CCMs between individuals~(5), 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.
机译：血管畸形被认为是导致血管增生性增生的单体疾病。在大脑中，由于内皮CCM蛋白质复合物失活，因此出现了脑海绵状畸形（CCMS），这是抑制激酶MEKK3〜（1-4）的活性所必需的。环境因素可以解释个人之间CCMS自然历史的差异〜（5），但为什么单一的CCMS经常表现出突然，快速增长，在中风或癫痫发作中，是未知的。在这里，我们表明CCMS的生长需要通过磷脂酰肌醇-3-激酶（PI3K）-MTOR途径以及CCM络合物的功能损失来增加信号传导。我们鉴定PIK3CA中的体细胞功能突变和在大多数人CCM中的CCM复合物中的CCM复合物中的功能突变。使用鼠标模型，我们表明CCMS的生长需要既有功能和CCM损失的内皮细胞功能，并且CCM丧失的功能和转录因子KLF4的表达增加（MEKK3的下游效应器）增强MTOR信号传导在内皮细胞中。与这些发现一致，MTORC1抑制剂雷帕霉素有效地阻断了小鼠模型中CCM的形成。我们建立了类似于癌症的三次受到癌症的机制，其中通过丧失血管“抑制基因”的血管生长和血管“癌基因的增益来产生激进的血管畸形，这会产生刺激过量的血管生长。这些发现表明，可以使用临床批准的MTORC1抑制剂治疗侵略性CCM。

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  • 来源
    《Nature》 |2021年第7862期|271-276|共6页
  • 作者

    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 Müller-Fielitz; Mei Chen; Patricia Mericko; Jisheng Yang; Derek C Sung; Michael T Lawton; J Michael Ruppert; Markus Schwaninger; Jakob Körbelin; Michael Potente; Issam A Awad; Douglas A Marchuk; Mark L Kahn;

  • 作者单位

    Department of Medicine and Cardiovascular Institute University of Pennsylvania;

    Department of Molecular Genetics and Microbiology Duke University School of Medicine;

    Department of Neurosurgery University of Pennsylvania;

    Department of Medicine and Cardiovascular Institute University of Pennsylvania;

    Angiogenesis and Metabolism Laboratory Max Planck institute for Heart and Lung Research;

    Department of Medicine and Cardiovascular Institute University of Pennsylvania;

    Department of Molecular Genetics and Microbiology Duke University School of Medicine;

    Neurovascular Surgery Program Section of Neurosurgery Department of Surgery The University of Chicago Medicine and Biological Sciences;

    Neurovascular Surgery Program Section of Neurosurgery Department of Surgery The University of Chicago Medicine and Biological Sciences;

    Neurovascular Surgery Program Section of Neurosurgery Department of Surgery The University of Chicago Medicine and Biological Sciences;

    Neurovascular Surgery Program Section of Neurosurgery Department of Surgery The University of Chicago Medicine and Biological Sciences;

    Neurovascular Surgery Program Section of Neurosurgery Department of Surgery The University of Chicago Medicine and Biological Sciences;

    Neurovascular Surgery Program Section of Neurosurgery Department of Surgery The University of Chicago Medicine and Biological Sciences;

    Department of Molecular Genetics and Microbiology Duke University School of Medicine;

    Department of Molecular Genetics and Microbiology Duke University School of Medicine;

    Institute for Experimental and Clinical Pharmacology and Toxicology Center of Brain Behavior and Metabolism University of Lübeck;

    Department of Medicine and Cardiovascular Institute University of Pennsylvania;

    Department of Medicine and Cardiovascular Institute University of Pennsylvania;

    Department of Medicine and Cardiovascular Institute University of Pennsylvania;

    Department of Medicine and Cardiovascular Institute University of Pennsylvania;

    Department of Neurosurgery The Barrow Neurological Institute;

    Cancer Institute West Virginia University;

    Institute for Experimental and Clinical Pharmacology and Toxicology Center of Brain Behavior and Metabolism University of Lübeck;

    University Medical Center Hamburg-Eppendorf Department of Oncology Hematology and Bone Marrow Transplantation;

    Angiogenesis and Metabolism Laboratory Max Planck institute for Heart and Lung Research|Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin corporate member of Freie Universität Berlin Humboldt-Universität zu Berlin|Max Delbrück Center for Molecular Medicine (MDC);

    Neurovascular Surgery Program Section of Neurosurgery Department of Surgery The University of Chicago Medicine and Biological Sciences;

    Department of Molecular Genetics and Microbiology Duke University School of Medicine;

    Department of Medicine and Cardiovascular Institute University of Pennsylvania;

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