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Decoding Heterogeneous and Coordinated Tissue Architecture in Glioblastoma Using Spatial Transcriptomics

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253080 | GEO | 2024/07/03

REPOSITORIES: GEO

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Project description:Glioblastoma (GBM) is the most common and malignant primary brain tumor. The extracellular matrix (ECM), also known as the matrisome, helps determine glioma invasion, adhesion, and growth. Little attention, however, has been paid to glycosylation of the ECM components that constitute the majority of glycosylated protein mass and presumed biological properties. To acquire a comprehensive understanding of the biological functions of the matrisome and its components, including proteoglycans and glycosaminoglycans (GAGs), in GBM tumorigenesis, and to identify potential biomarker candidates, we studied the alterations of GAGs, including heparan sulfate (HS) and chondroitin sulfate (CS), the core proteins of proteoglycans, and other glycosylated matrisomal proteins in GBM subtypes vs. control human brain tissue samples. We scrutinized the proteomics data to acquire in-depth site-specific glycoproteomic profiles of the GBM subtypes that will assist in identifying specific glycosylation changes in GBM. We observed an increase in CS 6-O sulfation and a decrease in HS 6-O sulfation, accompanied by an increase in unsulfated CS and HS disaccharides in GBM vs. control samples. Several core matrisome proteins, including proteoglycans (decorin, biglycan, agrin, prolargin, glypican-1, CSPG4), tenascin, fibronectin, hyaluronan link protein 1 and 2, laminins, and collagens, were differentially regulated in GBM vs. controls. Interestingly, a higher degree of collagen hydroxyprolination was also observed for GBM vs. controls. Further, two proteoglycans, CSPG4 and agrin, were significantly lower, about 6–fold for IDH-mutant compared to the WT GBM samples. Differential regulation of O-glycopeptides for proteoglycans, including brevican, neurocan, and versican, was observed for GBM subtypes vs. controls. Moreover, an increase in levels of glycosyltransferase and glycosidase enzymes was observed for GBM when compared to control samples. We also report distinct protein, peptide, and glycopeptide features for GBM subtypes comparisons. Taken together, our study informs understanding of the alterations to key matrisomal molecules that occur during GBM development.

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Decoding Heterogeneous and Coordinated Tissue Architecture in Glioblastoma Using Spatial Transcriptomics

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