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publication

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


Ren, A.A. et al.
Nature (2021)
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 activity. Environmental factors explain differences in CCM natural history between individuals, 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.



Authors

Ren, A.A., Snellings, D.A, Su, Y.S., Hong, C.C., Castro, M., Tang, A.T., Detter, M.R., Hobson, N., Girard, R., Romanos, S., Lightle, R., Moore, T., Shenkar, R., Benavides, C., Beaman, M.M., Mueller-Fielitz, H., Chen, M., Mericko, P., Yang, J., Sung, D.C., Lawton, M.T., Ruppert, M., Schwaninger, M., Körbelin, J., Potente, M., Awad, I.A., Marchuk, D.A., Kahn, M.L.



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