Abstract
BACKGROUND: Glioblastoma (GBM) is a highly lethal malignant intracranial tumor, distinguished from low-grade glioma by histopathological hallmarks such as pseudopalisading cells around necrosis (PAN) and microvascular proliferation (MVP). To date the spatial organization of the molecular and cellular components of these specific histopathological features has not been fully elucidated. METHODS: Here, using bulk RNA sequencing, spatial transcriptomic and single cell RNA sequencing (scRNA-seq) data of GBM patients, we identified niche-specific transcriptional programs and characterized the differences in molecular expression and cellular organization between PAN and MVP. RESULTS: Notably, we discovered spatially distinct domains within the tumor core and identified niche-specific signatures: NDRG1 and EPAS1, specifically expressed in the PAN and MVP regions. The clustering results showed two distinct phenotypes of endothelial cells (ECs) were enriched in the MVP and PAN regions, respectively. PAN-associated endothelial cells exhibit copy number variations similar to those in GBM cells. Single cell trajectory analysis reveals a pseudotime trajectory, indicating the differentiation of glioblastoma stem cells (GSCs) toward ECs. CONCLUSIONS: Necrosis cores which are surrounded by hypoxic and perivascular niches and microvascular proliferation area within the glioblastoma tumor microenvironment, have been considered as standardized morphological indicators of aggressive GBM. Our findings provide a cellular and molecular insights into GBM progression.