背景。肿瘤之间的相互作用,免疫,和血管壁龛在驱动胶质母细胞瘤(GBM)恶性肿瘤和治疗反应中起主要作用。组成,异质性,以及介导这种相互作用的细胞外核心基质蛋白(CMPs)的定位,然而,不是很了解。方法。这里,通过计算基因组学和蛋白质组学方法,我们分析了GBM中CMP表达的功能和临床相关性,单细胞,和空间解剖学分辨率。结果。我们鉴定了编码CMP的基因,其表达水平将GBM肿瘤分为CMP表达高(M-H)和CMP表达低(M-L)组。CMP富集与更差的患者生存率相关,特定的驱动致癌改变,间充质状态,肿瘤前免疫细胞浸润,和免疫检查点基因表达。解剖学和单细胞转录组分析表明,基质基因表达富集在血管和前缘/浸润性壁ni中,已知它们含有驱动GBM进展的神经胶质瘤干细胞。最后,我们确定了17个基因的CMP表达特征,称为Matrisome17(M17)签名,进一步完善CMP基因的预后价值。与MGMT启动子甲基化状态以及典型亚型相比,M17签名是一个明显更强的预后因素。而且重要的是,可能预测对PD1封锁的反应。结论。基质基因表达签名通过可以介导间充质-免疫串扰的功能相关GBM小生境的存活和潜在生物标志物提供了GBM患者的稳健分层。基于矩阵概况的患者分层可以有助于治疗策略的选择和优化。
UNASSIGNED: Interactions among tumor, immune, and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood.
UNASSIGNED: Here, through computational genomics and proteomics approaches, we analyzed the functional and clinical relevance of CMP expression in GBM at bulk, single cell, and spatial anatomical resolution.
UNASSIGNED: We identified genes encoding CMPs whose expression levels categorize GBM tumors into CMP expression-high (M-H) and CMP expression-low (M-L) groups. CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells, and immune checkpoint gene expression. Anatomical and single-cell transcriptome analyses indicate that
matrisome gene expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene CMP expression signature, termed
Matrisome 17 (M17) signature that further refines the prognostic value of CMP genes. The M17 signature is a significantly stronger prognostic factor compared to MGMT promoter methylation status as well as canonical subtypes, and importantly, potentially predicts responses to PD1 blockade.
UNASSIGNED: The
matrisome gene expression signature provides a robust stratification of GBM patients by survival and potential biomarkers of functionally relevant GBM niches that can mediate mesenchymal-immune cross talk. Patient stratification based on
matrisome profiles can contribute to selection and optimization of treatment strategies.