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Abstract：
Because of the heterogeneity of lower-grade gliomas (LGGs), patients show various survival outcomes that are not reliably predicted by histological classification. The tumour microenvironment (TME) contributes to the initiation and progression of brain LGGs. Identifying potential prognostic markers based on the immune and stromal components in the TME will provide new insights into the dynamic modulation of these two components of the TME in LGGs. We applied ESTIMATE to calculate the ratio of immune and stromal components from The Cancer Genome Atlas database. After combined differential gene expression analysis, protein-protein interaction network construction and survival analysis, CD44 was screened as an independent prognostic factor and subsequently validated utilizing data from the Chinese Glioma Genome Atlas database. To decipher the association of glioma cell CD44 expression with stromal cells in the TME and tumour progression, RT-qPCR, cell viability and wound healing assays were employed to determine whether astrocytes enhance glioma cell viability and migration by upregulating CD44 expression. Surprisingly, M1 macrophages were identified as positively correlated with CD44 expression by CIBERSORT analysis. CD44+ glioma cells were further suggested to interact with microglia-derived macrophages (M1 phenotype) via osteopontin signalling on the basis of single-cell sequencing data. Overall, we found that astrocytes could elevate the CD44 expression level of glioma cells, enhancing the recruitment of M1 macrophages that may promote glioma stemness via osteopontin-CD44 signalling. Thus, glioma CD44 expression might coordinate with glial activities in the TME and serve as a potential therapeutic target and prognostic marker for LGGs.
摘要：
由于低级别胶质瘤（LGGs）的异质性，患者表现出各种无法通过组织学分类可靠预测的生存结局.肿瘤微环境(TME)有助于脑LGG的启动和进展。基于TME中的免疫和基质成分鉴定潜在的预后标志物将为LGG中TME的这两种成分的动态调节提供新的见解。我们应用ESTIMATE来计算来自癌症基因组图谱数据库的免疫和基质成分的比率。结合差异基因表达分析后，蛋白质相互作用网络的构建和生存分析,CD44被筛选为独立的预后因子，随后利用中国胶质瘤基因组图谱数据库的数据进行验证。为了破译TME和肿瘤进展中胶质瘤细胞CD44表达与基质细胞的关系，RT-qPCR,细胞活力和伤口愈合试验用于确定星形胶质细胞是否通过上调CD44表达来增强神经胶质瘤细胞活力和迁移。令人惊讶的是,通过CIBERSORT分析，M1巨噬细胞与CD44表达呈正相关。在单细胞测序数据的基础上,进一步提示CD44+神经胶质瘤细胞通过骨桥蛋白信号传导与小胶质细胞衍生的巨噬细胞(M1表型)相互作用。总的来说,我们发现星形胶质细胞可以提高胶质瘤细胞的CD44表达水平，增强M1巨噬细胞的募集，这可能通过骨桥蛋白-CD44信号传导促进神经胶质瘤的干性。因此，胶质瘤CD44的表达可能与TME中的胶质细胞活性协调，并可作为LGGs的潜在治疗靶标和预后标志物。
