Decoding Heterogeneous and Coordinated Tissue Architecture in Glioblastoma Using Spatial Transcriptomics. Decoding Heterogeneous and Coordinated Tissue Architecture in Glioblastoma Using Spatial Transcriptomics

Glioblastoma multiforme (GBM) stands as a devastating human malignancy known for its aggressive nature and resistance to multiple therapeutic interventions. Despite extensive intra-tumor heterogeneity unveiled by single-cell transcriptomic studies, the spatial intricacies of this heterogeneity remain largely unknown. This study leveraged clinical GBM specimens to explore gene expression heterogeneity using spatial transcriptomics technology. Our findings unveiled a prominent enrichment of the tissue stem cell signature in the region between necrosis and the peritumoral area, exhibiting a positive correlation with the signature of the mesenchymal subtype. Additionally, the upregulated genes in these regions demonstrated associations with ECM-receptor interaction, Proteoglycans, as well as the VEGF and ANGPT signaling pathways. In contrast, signature genes linked to Glycogen metabolism and Oxidative Phosphorylation were prominently expressed across all samples, irrespective of pathological zoning. Notably, Creatine metabolism showed enrichment in various cell populations except for the vascular-enriched areas. These spatial profiles not only serve as a reference but also provide a profound guide for future functional and mechanistic investigations into the progression of GBM. Overall design: Tumor tissues were procured from patients diagnosed with treatment-naive GBM (WHO Grade IV). For ST sequencing, 16 fresh tissue samples were extracted via surgery from 3 glioblastoma patients.

多形性胶质母细胞瘤（Glioblastoma multiforme, GBM）是一种极具破坏性的人类恶性肿瘤，以极强的侵袭性和对多种治疗手段的耐药性为显著特征。尽管单细胞转录组学研究已揭示其广泛存在的肿瘤内异质性，但该异质性的空间复杂性仍在很大程度上尚未被阐明。本研究借助临床GBM标本，采用空间转录组学技术探究其基因表达异质性。研究结果显示，坏死区与瘤周区域交界的组织中显著富集了组织干细胞基因特征集，且该特征与间质性亚型的特征呈正相关。此外，这些区域的上调基因与细胞外基质-受体相互作用通路、蛋白聚糖通路，以及血管内皮生长因子（VEGF）和血管生成素（ANGPT）信号通路密切相关。与之相反，与糖原代谢和氧化磷酸化相关的特征基因在所有样本中均呈高表达，且不受病理分区的影响。值得注意的是，肌酸代谢特征在除血管富集区域外的各类细胞群中均存在富集现象。这些空间表达谱不仅可作为参考依据，更为未来针对GBM进展的功能与机制研究提供了重要指导。研究整体设计如下：本研究的肿瘤组织均取自未经治疗的初诊GBM（WHO Ⅳ级）患者。在空间转录组（Spatial Transcriptomics, ST）测序中，研究人员从3名胶质母细胞瘤患者的手术标本中获取了16份新鲜组织样本。