Functional Merlin Depletion Defines a TEAD1-Dependent Tumor Cell State that Promotes Schwannoma Progression: Xenium spatial transcriptomics

Intratumoral heterogeneity has been observed in VS at the transcriptional, protein expression, and cellular proliferative potential levels, highlighting the need to elucidate the mechanisms underlying heterogeneity in tumor Schwann cell merlin inactivation and therapeutic resistance. Using integrated single-cell multi-omic profiling across NF2-related (VSnf2) and sporadic (VSspo) schwannomas, we identified functional merlin depletion as a continuous, spatially organized, plastic tumor Schwann cell state, rather than a binary genetic event.

A transcriptomic merlin depletion score (MDS) captured this gradient, and merlin-depleted tumor Schwann cells were identified as a potential source of proliferative, angiogenic, and macrophage-recruiting signals. Lineage trajectory and multi-omic regulatory modeling identified the transcription factor TEAD1 as a potential regulator of MDS states and signaling pathways underlying tumor progression. Pharmacologic TEAD auto-palmitoylation inhibitors disrupted TEAD1–YAP/TAZ interactions, reversed merlin-loss transcriptional programs, suppressed VEGFA, NRG1, IL-34, and CSF1 signaling, and selectively attenuated tumor cell viability in human Schwann tumor cultures and in a mouse model.