Multi-omic Analysis of Sporadic Vestibular Schwannoma Reveals a Nerve Injury-Like State and Novel Molecular Targets

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Introduction: Sporadic vestibular schwannomas (VS) are benign tumors but can lead to significant neurologic and otologic morbidity. The treatment for growing or symptomatic VS consists of radiosurgery or open surgical resection, both of which are associated with morbidity. At present, the underlying VS tumor pathophysiology, particularly regarding the tumor microenvironment (TME) and its role in pathogenesis, remains poorly understood, making it challenging to devise alternative treatment strategies for VS. Methods: We performed single cell RNA sequencing (scRNA-seq) on 15 VS samples with paired single cell ATAC sequencing (scATAC-seq, n = 6) and whole exome sequencing (WES, n = 12), thus providing a high-resolution transcriptional and epigenetic characterization of the VS TME ([ Fig. 1 ]). We then used these findings to perform deconvolution analysis and unsupervised clustering of bulk RNA expression data from a multi-institutional cohort of 175 tumors divided into discovery and validation cohorts. We also performed enrichment and ligand-receptor analysis at the single cell level using our scATAC-seq and scRNA-seq data to identify biologically relevant transcription factors and signaling cascades. Finally, we performed in vitro functional assays to validate our in silico findings. Results: Single cell analysis revealed significant diversity among tumor Schwann cell (SC), stromal and immune populations in the VS TME ([ Fig. 2 ]). Subcluster analysis of VS SCs identified several cell states such as hypoxia, myelinating, repair-like and MHC-II antigen presenting SCs ([ Fig. 3a ]). Copy number analysis at the single cell level showed that cells with chr22q loss shared the same transcriptional metaprograms with chr22q balanced cells rather than forming a unique cluster, suggesting that VS-SC functional states overlap regardless of CNA status ([ Fig. 3b ]). Interestingly, we found that VS tumor SCs closely resemble SCs identified in murine nerve injury models and that repair-like and MHC-II antigen presenting subtype SCs are associated with increased myeloid cell infiltrate, implicating a nerve injury-like process in VS pathogenesis ([ Fig. 3c ]). Bulk RNA expression analysis revealed two VS tumor subtypes, with myeloid cell enriched tumors being associated with larger tumor size (Injury-like tumors). At the molecular level, scATAC-seq identified transcription factors associated with Injury-like tumors such as SMARCC1, FOSL1 and RUNX1 and ligand-receptor analysis suggested that SCs may recruit myeloid cells via CSF1 signaling, which was enriched in Injury-like tumors ([ Fig. 4a ]). Conditioned media from immortalized human Schwann cells promoted the migration and proliferation of monocytes in vitro , suggesting that secreted SC factors may influence both processes. Inhibition of CSF1 signaling reduced both proliferation and migration of immune cells grown in conditioned media ([ Fig. 4b ]). Conclusions: Our findings identify two molecular subtypes of sporadic VS. In the Injury-like subtype, which is enriched for myeloid cells, tumor growth may be driven by recruitment of myeloid cells via CSF1 signaling from VS SCs expressing transcription factors such as SMARCC1. Taken together, our results identify promising molecular targets for therapies aimed at treating sporadic VS. Fig. 1 Fig. 2 Fig. 3 Fig. 4 Publication History Article published online: 05 February 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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