Spatial architecture of high-grade glioma reveals tumor heterogeneity within distinct domains

High-grade gliomas are aggressive primary brain cancers with poor response to standard regimens, driven by immense heterogeneity. In isocitrate dehydrogenase (IDH) wild-type high-grade glioma (glioblastoma, GBM), increased intra-tumoral heterogeneity is associated with more aggressive disease. Recently, spatial technologies have emerged to dissect this complex heterogeneity within the tumor ecosystem by preserving cellular organization in situ. Here, we construct a high- resolution molecular landscape of GBM and IDH-mutant high-grade glioma patient samples to investigate the cellular subtypes and spatial communities that compose high-grade glioma using digital spatial profiling and spatial molecular imaging. This uncovered striking diversity of the tumor and immune microenvironment, that is embodied by the heterogeneity of the inferred copy- number alterations in the tumor. Reconstructing the tumor architecture revealed brain-intrinsic niches, composed of tumor cells reflecting brain cell types and microglia; and brain-extrinsic niches, populated by mesenchymal tumor cells and monocytes. We further reveal that cellular communication in these niches is underpinned by specific ligand-receptor pairs. This primary study reveals high levels of intra-tumoral heterogeneity in high-grade gliomas, associated with a diverse immune landscape within spatially localized regions.

高级胶质瘤是具有侵袭性且对常规治疗方案反应不良的原发性脑部恶性肿瘤，其发展受到巨大异质性的驱动。在IDH野生型高级胶质瘤（胶质母细胞瘤，GBM）中，肿瘤内异质性的增加与更侵袭性的疾病相关。近年来，空间技术已出现，通过保留原位细胞组织结构，解析肿瘤生态系统中的复杂异质性。在此，我们构建了GBM和IDH突变型高级胶质瘤患者样本的高分辨率分子景观，以利用数字空间分析和空间分子成像技术，研究构成高级胶质瘤的细胞亚型和空间群落。这一发现揭示了肿瘤及其免疫微环境的显著多样性，这体现在肿瘤中推断出的拷贝数变异的异质性。重建肿瘤结构揭示了脑内性生态位，由反映脑细胞类型和微胶质细胞的肿瘤细胞组成；以及脑外性生态位，由间充质肿瘤细胞和单核细胞占据。我们进一步揭示，这些生态位中的细胞通讯由特定的配体-受体对支撑。这一基础研究揭示了高级胶质瘤中肿瘤内异质性的高度，与空间定位区域内多样的免疫景观相关。