2. Academic Validation
  3. PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism

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

  • Nature. 2021 Jun;594(7862):271-276. doi: 10.1038/s41586-021-03562-8.
Aileen A Ren  # 1,  Daniel A Snellings  # 2,  Yourong S Su 3,  Courtney C Hong 1,  Marco Castro 4,  Alan T Tang 1,  Matthew R Detter 2,  Nicholas Hobson 5,  Romuald Girard 5,  Sharbel Romanos 5,  Rhonda Lightle 5,  Thomas Moore 5,  Robert Shenkar 5,  Christian Benavides 2,  M Makenzie Beaman 2,  Helge Müller-Fielitz 6,  Mei Chen 1,  Patricia Mericko 1,  Jisheng Yang 1,  Derek C Sung 1,  Michael T Lawton 7,  J Michael Ruppert 8,  Markus Schwaninger 6,  Jakob Körbelin 9,  Michael Potente 4 10 11,  Issam A Awad 5,  Douglas A Marchuk 12,  Mark L Kahn 13
Affiliations

Affiliations

  • 1 Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
  • 3 Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Angiogenesis and Metabolism Laboratory, Max Planck institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 5 Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
  • 6 Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany.
  • 7 Department of Neurosurgery, The Barrow Neurological Institute, Phoenix, AZ, USA.
  • 8 Cancer Institute, West Virginia University, Morgantown, WV, USA.
  • 9 University Medical Center Hamburg-Eppendorf, Department of Oncology, Hematology and Bone Marrow Transplantation, Hamburg, Germany.
  • 10 Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • 11 Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.
  • 12 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA. douglas.marchuk@duke.edu.
  • 13 Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA. markkahn@pennmedicine.upenn.edu.
  • # Contributed equally.
PMID: 33910229 DOI: 10.1038/s41586-021-03562-8
Abstract

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.

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