YAP-TEAD-driven CPA4 promotes NF2-deficient meningioma growth

Neurofibromin 2 (NF2) deficiency is a driver of meningioma and other cancers, yet transcriptional effectors that sustain NF2-deficient tumors remain poorly defined. We identify carboxypeptidase A4 (CPA4) as an effector of YAP-TEAD signaling in NF2-deficient meningioma. Transcriptomic profiling identified CPA4 as a consistently upregulated effector. Across patient cohorts and specimens, CPA4 expression was enriched in NF2 -mutant and chromosome 22q-deleted meningiomas and associated with higher tumor grade and chromosome 1p loss. CPA4 depletion impaired proliferation, disrupted cell-cycle, DNA-replication, and DNA-repair programs, suppressed intracranial tumor growth, and prolonged survival. Integrated epigenomic and functional assays identified CPA4 as a direct YAP-TEAD transcriptional target. CPA4-high meningioma models exhibited preferential sensitivity to YAP-TEAD inhibition, while verteporfin and the clinical-stage TEAD inhibitor VT3989 reduced CPA4 expression, suppressed orthotopic tumor growth, and prolonged survival. These findings uncover a targetable YAP-TEAD-CPA4 dependency in NF2-deficient meningioma and identify CPA4 as a potential biomarker for TEAD- directed therapy.

CPA4 links NF2 loss to oncogenic YAP-TEAD transcription, sustains meningioma growth, and marks tumor sensitivity to pharmacologic TEAD inhibition. These findings establish CPA4 as a tumor-promoting effector and potential biomarker of an actionable pathway shared across NF2- deficient cancers.