不同前庭神经鞘瘤亚型中施万细胞-免疫细胞轨迹的差异反映神经损伤-修复程序

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中文摘要

背景： 尽管施万细胞（SCs）日益被认为积极参与癌症进展，但其驱动前庭神经鞘瘤（VS）发生的细胞自主致癌机制仍不明确。此外，肿瘤微环境（TME）内的异质性在VS发病机制中的作用仍不清楚。方法：在本研究中，我们对散发性VS和NF2相关神经鞘瘤病（NF2-SWN）VS进行了整合多组学分析，采用bulk RNA测序、单核RNA测序（snRNA-seq）、DNA甲基化谱分析和免疫组织化学（IHC）。结果：转录组和DNA甲基化谱分析鉴定出两个不同的分子亚组，即免疫富集型神经鞘瘤（IES）和免疫耗竭型神经鞘瘤（IDS），且独立于综合征状态。我们开发了多基因和基于IHC的分类器，可稳健区分这两个分子亚组。值得注意的是，我们发现VS亚组之间在临床特征和预后结局方面存在显著差异。此外，snRNA-seq揭示了VS微环境内的细胞异质性，其中SCs和免疫细胞的表型转变密切再现了神经损伤和修复的连续阶段。结论：总体而言，我们的研究揭示，肿瘤微环境内SC可塑性和免疫细胞动态促成了前庭神经鞘瘤的瘤间异质性，为肿瘤进展和神经损伤-修复程序背后的生物学过程提供了见解。

英文摘要

Although Schwann cells (SCs) are increasingly recognised as active contributors to cancer progression, their cell-autonomous oncogenic mechanisms underlying vestibular schwannoma (VS) development remain poorly defined. Moreover, the roles of heterogeneity within the tumour microenvironment (TME) in VS pathogenesis remain unclear. In this study, we performed integrative multi-omic analyses of sporadic VSs and NF2-related schwannomatosis (NF2-SWN) VSs, using bulk RNA-sequencing, single-nucleus RNA-sequencing (snRNA-seq), DNA methylation profiling, and immunohistochemistry (IHC). Transcriptomic and DNA methylation profiling analyses identified two distinct molecular subgroups, immune-enriched schwannoma (IES) and immune-depleted schwannoma (IDS), independent of syndromic status. We developed multigene and IHC-based classifiers that robustly distinguish the two molecular subgroups. Notably, we found significant differences in clinical characteristics and prognostic outcomes across VS subgroups. Furthermore, snRNA-seq revealed cellular heterogeneity within the VS microenvironment, with phenotypic transitions in SCs and immune cells that closely recapitulated the sequential stages of nerve injury and repair. Collectively, our study reveals that SC plasticity and immune cell dynamics within the tumor microenvironment contribute to intertumoral heterogeneity in vestibular schwannomas, offering insights into the biological processes underlying tumor progression and nerve injury-repair programs.