Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state [scATAC-seq]. Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state [scATAC-seq]

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to the pathogenesis of these tumors remains poorly understood. We performed scRNA-seq on 15 VS samples, with paired scATAC-seq (n=6) and exome sequencing (n=12). We identified diverse Schwann cell (SC), stromal, and immune populations in the VS TME and found that repair-like and MHC-II antigen presenting subtype SCs are associated with increased myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution of RNA-expression data from 195 tumors revealed Injury-like tumors are associated with larger tumor size, and scATAC-seq identified transcription factors associated with nerve repair among SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggested that SCs recruit monocytes. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be targeted to prevent tumor progression. This SubSeries is part of a SuperSeries (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE216784). Matching whole exome sequencing data is available via NCBI dbGaP (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA981645/). Overall design: Single-cell ATAC-seq data was performed on sporadic vestibular schwannoma tumors. There are no experimental groups, controls or references.

前庭神经鞘瘤（Vestibular schwannomas, VS）是一类良性肿瘤，可引发严重的神经及耳科功能损害。目前，VS的异质性及其肿瘤微环境（tumor microenvironment, TME）对肿瘤发病机制的贡献仍不甚明确。本研究对15例VS样本开展了单细胞RNA测序（single-cell RNA sequencing, scRNA-seq），并配套完成了6例样本的单细胞转座酶可及性测序（single-cell assay for transposase-accessible chromatin sequencing, scATAC-seq）及12例样本的外显子组测序。研究人员在VS的肿瘤微环境中鉴定出多种雪旺细胞（Schwann cell, SC）、基质细胞及免疫细胞群，并发现修复型与MHC-II抗原呈递亚型的雪旺细胞与髓系细胞浸润程度升高显著相关，提示该过程存在类似神经损伤的分子机制。通过对195例肿瘤的RNA表达数据进行反卷积分析，本研究发现损伤型肿瘤与更大的肿瘤体积存在关联；单细胞ATAC测序则鉴定出损伤型肿瘤来源的雪旺细胞中参与神经修复的转录因子。配体-受体分析与体外实验结果表明，雪旺细胞可招募单核细胞。本研究证实，损伤型雪旺细胞可能通过招募髓系细胞促进肿瘤生长，并鉴定出可用于干预肿瘤进展的分子通路。本子系列隶属于对应超级系列（https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE216784）。匹配的全外显子组测序数据可通过NCBI dbGaP数据库获取（https://www.ncbi.nlm.nih.gov/bioproject/PRJNA981645/）。整体实验设计：针对散发性前庭神经鞘瘤样本开展单细胞ATAC测序，本研究未设置实验组、对照组及参考样本。