Angiogenic switching in cerebral cavernous malformations driven by MAP3K3-PIK3CA synergy

Area of Science:

• Neuroscience
• Genetics
• Oncology

Background:

• Cerebral cavernous malformations (CCMs) are common CNS vascular anomalies causing seizures and stroke.
• Both familial (CCM1-3 mutations) and sporadic (MAP3K3, PIK3CA mutations) forms exist, but mechanisms are unclear.
• No effective medical therapies are currently available for CCMs.

Purpose of the Study:

• To investigate the cooperative effects of MAP3K3 and PIK3CA mutations in CCM pathogenesis.
• To explore potential therapeutic strategies targeting these mutations.

Main Methods:

• Utilized transgenic neonatal and adult mouse models with specific MAP3K3 and PIK3CA mutations.
• Employed histology, micro-CT, bulk and single-cell RNA sequencing.
• Analyzed human CCM samples and patient-derived organoids.

Main Results:

• MAP3K3 mutations activated inflammatory and angiogenic pathways; PIK3CA mutations enhanced cell cycle progression.
• Double mutations synergistically amplified PI3K-AKT-mTOR signaling, inducing an "angiogenic switch" promoting lesion development.
• Transcriptomic analysis of human CCMs confirmed enrichment of angiogenesis signatures in lesions with double mutations.

Conclusions:

• Convergent MAPK and PI3K pathway activation drives CCM pathogenesis.
• PI3Kα inhibition, using alpelisib, suppressed lesion formation and reversed pro-angiogenic signaling.
• PI3Kα inhibition represents a potential therapeutic strategy for CCMs.