Variable Schwann cell merlin inactivation is targetable with TEAD1 inhibition in schwannomas

Schwann cell tumors occur frequently in association with the vestibular nerves, leading to sensorineural hearing loss, and brainstem compression. In humans, unilateral vestibular schwannomas (VS) occur sporadically (VS ^spo ) ¹ , or bilaterally with neurofibromatosis type 2 syndrome (NF2) – VS ^nf2 . ² VS formation is driven by sub-haploid NF2 gene dosage ³ , typically by biallelic loss. ^4,5 Loss of merlin promotes hippo/TEAD dependent transcriptional reprogramming, proliferation, and paracrine signaling that varies across time, and tumor volume. ^4,6 These variations lead to a clinically unpredictable course, and incomplete response to treatment. We hypothesized that Schwann cell merlin inactivation state determines cell-wise hippo/TEAD dependency and drives schwannoma pathogenesis. We analyzed clinical samples from VS ^spo and VS ^nf2 with a multi-omics approach and detected variation in merlin activity within tumor Schwann cell population. We found that tumor-driving merlin-depleted Schwann cells (Schwann ^mer- ) exhibited elevated hippo activity that was predominantly driven by TEAD1. In-silico TEAD1 perturbation led to a reversal to merlin intact Schwann phenotype. These findings, and tumor cell growth suppression were confirmed in NF2 ^{fl/fl;Peri-Cre} mouse model ⁷ , and in human derived schwannoma cells treated with a pan-TEAD auto palmitoylation inhibitor VT3989. ⁸ Our computational and experimental results confirm that TEAD1 inhibition could be a potent, targeted strategy for schwannomas.