Spatial and single-cell characterization of human glioblastoma tumor microenvironment reveals malignant cellular...

Understanding the complex cellular and spatial organization of glioblastoma (GBM) and its microenvironment is crucial for improving diagnosis and treatment. Here we integrated 121 spatial transcriptomics, single-cell RNA sequencing, single-cell assay for transposase-accessible chromatin using sequencing and patch sequencing profiles from 100 patients to characterize primary GBM tissue. We identified four malignant cellular communities that exhibited consistent patterns of cell-type compositions, gene expression and intercellular interactions across patients. We identified two subpopulations of mesenchymal-like (MES-like) tumor cells: MES-Hyp, colocalized with monocyte-derived brain macrophages in hypoxic regions; and MES-Ast, associated with endothelial cells, pericytes and vascular smooth muscle cells. We also predicted and experimentally verified cell subtypes and ligand-receptor pairs involved in intercellular communications in each cellular community. Furthermore, patch sequencing analysis revealed that synaptic connections with glioma cells were predominantly formed between neurons and oligodendrocyte-progenitor-like tumor cells. Overall, our study provides insights into the spatial organization and intercellular communication in GBM, offering potential therapeutic targets.