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

• Published in: Nature (London) Vol. 594; no. 7862; pp. 271 - 276
• Main Authors: Ren, Aileen A., Snellings, Daniel A., Su, Yourong S., Hong, Courtney C., Castro, Marco, Tang, Alan T., Detter, Matthew R., Hobson, Nicholas, Girard, Romuald, Romanos, Sharbel, Lightle, Rhonda, Moore, Thomas, Shenkar, Robert, Benavides, Christian, Beaman, M. Makenzie, Müller-Fielitz, Helge, Chen, Mei, Mericko, Patricia, Yang, Jisheng, Sung, Derek C., Lawton, Michael T., Ruppert, J. Michael, Schwaninger, Markus, Körbelin, Jakob, Potente, Michael, Awad, Issam A., Marchuk, Douglas A., Kahn, Mark L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-06-2021; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13; 13/51; 13/95; 14; 38; 42; 45; 45/23; 59; 631/443/592/75/593/1370/534; 64; 692/308/575; 692/617/375/1370/534; 692/699/75/593/1370/534; Animal models; Animals; Animals, Newborn; Blood vessels; Brain; Cancer; Ccm protein; Cell growth; Class I Phosphatidylinositol 3-Kinases - genetics; Class I Phosphatidylinositol 3-Kinases - metabolism; Development and progression; Disease Models, Animal; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Environmental factors; Gain of Function Mutation; Genes; Genetic aspects; Health aspects; Hemangioma, Cavernous; Hemangioma, Cavernous, Central Nervous System - blood supply; Hemangioma, Cavernous, Central Nervous System - genetics; Hemangioma, Cavernous, Central Nervous System - metabolism; Hemangioma, Cavernous, Central Nervous System - pathology; Humanities and Social Sciences; Humans; Inactivation; Kinases; KLF4 protein; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors - metabolism; Loss of Function Mutation; Male; MAP Kinase Kinase Kinase 3 - metabolism; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; multidisciplinary; Mutation; Mutation (Biology); Neoplasms - blood supply; Neoplasms - genetics; Neoplasms - pathology; Phosphotransferases; Physiological aspects; Rapamycin; Science; Science (multidisciplinary); Seizures; Signal transduction; Signaling; Sirolimus - pharmacology; Stroke; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription factors; Germany
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03562-8

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.
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.