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

NF2 deficiency is a known driver of meningioma and other cancers, but the transcriptional effectors that sustain these tumors are poorly understood. In this bioRxiv preprint, researchers used transcriptomic profiling to identify carboxypeptidase A4 (CPA4) as a consistently upregulated effector of YAP-TEAD signaling in NF2-deficient meningioma. CPA4 expression was enriched in NF2-mutant and chromosome 22q-deleted meningiomas across patient cohorts and was associated with higher tumor grade and chromosome 1p loss, suggesting clinical relevance.

Functional experiments showed that CPA4 depletion impaired proliferation, disrupted cell-cycle, DNA-replication, and DNA-repair programs, suppressed intracranial tumor growth, and prolonged survival in model systems. Integrated epigenomic and functional assays confirmed CPA4 as a direct YAP-TEAD transcriptional target. Notably, CPA4-high meningioma models were preferentially sensitive to YAP-TEAD inhibition, and both verteporfin and the clinical-stage TEAD inhibitor VT3989 reduced CPA4 expression, suppressed orthotopic tumor growth, and prolonged survival.

These results uncover a targetable YAP-TEAD-CPA4 dependency in NF2-deficient meningioma and identify CPA4 as a potential biomarker for selecting patients likely to benefit from TEAD-directed therapies. The study provides a rationale for further clinical evaluation of TEAD inhibitors in this molecular subtype of meningioma.