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

Area of Science:

• Vascular biology
• Molecular genetics
• Oncology

Background:

• Cerebral cavernous malformations (CCMs) are vascular malformations linked to CCM protein complex inactivation.
• The rapid growth and clinical sequelae of CCMs, such as strokes and seizures, remain poorly understood.
• Understanding the molecular drivers of CCM growth is crucial for developing effective treatments.

Purpose of the Study:

• To elucidate the molecular mechanisms driving the rapid growth of cerebral cavernous malformations.
• To identify key signaling pathways and genetic alterations involved in CCM pathogenesis.
• To explore potential therapeutic targets for aggressive CCMs.

Main Methods:

• Analysis of human CCM samples for somatic mutations in PIK3CA and CCM complex genes.
• Utilized mouse models to investigate the roles of PI3K-mTOR signaling and CCM complex function in endothelial cells.
• Assessed the efficacy of the mTORC1 inhibitor rapamycin in blocking CCM formation in vivo.

Main Results:

• CCM growth requires increased PI3K-mTOR signaling and loss of CCM complex function.
• Somatic gain-of-function mutations in PIK3CA and loss-of-function mutations in the CCM complex were identified in the same cells in human CCMs.
• CCM loss of function and KLF4 expression augment endothelial mTOR signaling, and rapamycin treatment inhibited CCM formation in mouse models.

Conclusions:

• A three-hit mechanism, analogous to cancer, involving loss of tumor suppressors and gain of an oncogene drives aggressive CCMs.
• Targeting the PI3K-mTOR pathway with mTORC1 inhibitors represents a potential therapeutic strategy for aggressive CCMs.
• Clinically approved mTORC1 inhibitors may be repurposed for treating aggressive cerebral cavernous malformations.