PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism
| Autor: | Thomas R. Moore, Nicholas Hobson, Rhonda Lightle, Mark L. Kahn, Romuald Girard, Michael T. Lawton, Marco Castro, Courtney C. Hong, Jakob Körbelin, Derek C. Sung, M. Makenzie Beaman, Mei Chen, Issam A. Awad, Yourong S. Su, Alan T. Tang, Robert Shenkar, Markus Schwaninger, Douglas A. Marchuk, Daniel A. Snellings, Matthew R Detter, Sharbel Romanos, Christian R Benavides, Michael Potente, Jisheng Yang, Aileen A. Ren, J. Michael Ruppert, Patricia Mericko, Helge Müller-Fielitz |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Hemangioma Cavernous Central Nervous System Class I Phosphatidylinositol 3-Kinases Kruppel-Like Transcription Factors mTORC1 MAP Kinase Kinase Kinase 3 Biology Mechanistic Target of Rapamycin Complex 1 medicine.disease_cause Article 03 medical and health sciences Kruppel-Like Factor 4 Mice 0302 clinical medicine Loss of Function Mutation Neoplasms medicine Animals Humans Transcription factor Loss function PI3K/AKT/mTOR pathway Sirolimus Mutation Multidisciplinary Oncogene Effector TOR Serine-Threonine Kinases Endothelial Cells Disease Models Animal 030104 developmental biology Animals Newborn KLF4 030220 oncology & carcinogenesis Gain of Function Mutation Cancer research |
| Zdroj: | Nature |
| ISSN: | 1476-4687 |
| Popis: | 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 MEKK31–4. 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. Aggressive cerebral cavernous malformations (CCMs) are found to grow through a three-hit cancer-like mechanism, involving gain of function of a gene that promotes vascular growth, and loss of function of genes that suppress it. |
| Databáze: | OpenAIRE |
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