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A gel-top model for characterizing the mesenchymal features of glioblastoma cells

ABSTRACT: Glioblastoma (GBM) remains one of the most aggressive adult cancers, with limited treatment options due to an incomplete understanding of its biology. GBM exhibits different transcriptional subtypes, among which the mesenchymal (mGBM) variant is associated with particularly aggressive nature and poor outcomes. Developing models that capture mGBM phenotypes could offer new insights into its biology and therapeutic vulnerabilities. However, the lack of in vitro models for mGBM has posed challenges in investigating the aggressive GBM subtype. Here, we present a gel-top culture model in which GBM cells exhibit MES features, including distinct transcriptomic profiles, invasive phenotypes, cell morphology, cytoskeletal organization, and gene expression linked to cell-extracellular matrix interactions. Furthermore, co-culturing GBM cells with microglia in this system revealed enhanced microglial recruitment and interaction, effectively recapitulating the tumor microenvironment of mGBM that traditional 2D culture fails to model. Using the bioinformatic tool Small Molecule Suite, we identified casein kinase 2 (CK2) as a targetable molecule in GBM cells within our system, potentially driving MES features. Notably, CK2 inhibitors reduced the mesenchymal signature of mGBM cells, suggesting their potential as a targeted therapy for mGBM. Together, our findings suggest that the gel-top culture model replicates key features of mGBM, serving as a valuable platform for studying its biology and identifying novel therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292931 | GEO | 2025/04/03

REPOSITORIES: GEO

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Project description:Glioblastoma (GBM) is a common and deadly form of brain tumor in adults. Dysregulated metabolism in GBM offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome, and the glycoproteome of human subgroup-specific GBM sphere-forming cells (GSC). L-fucose abundance and core fucosylation activation were elevated in mesenchymal (MES) compared with proneural GSCs; this pattern was retained in subgroup-specific xenografts and in subgroup-affiliated human patient samples. Genetic and pharmacological inhibition of core fucosylation significantly reduced tumor growth in MES GBM preclinical models. Liquid chromatography-mass spectrometry (LC-MS)-based glycoproteomic screening indicated that most MES-restricted core-fucosylated proteins are involved in therapeutically relevant GBM pathological processes, such as extracellular matrix interaction, cell adhesion, and integrin-mediated signaling. Selective L-fucose accumulation in MES GBMs was observed using preclinical minimally invasive PET, implicating this metabolite as a potential subgroup-restricted biomarker.Overall, these findings indicate that L-fucose pathway activation in MES GBM is a subgroup-specific dependency that could provide diagnostic markers and actionable therapeutic targets.<h4>SIGNIFICANCE: Metabolic characterization of subgroup-specific glioblastoma (GBM) sphere-forming cells identifies the L-fucose pathway as a vulnerability restricted to mesenchymal GBM, disclosing a potential precision medicine strategy for targeting cancer metabolism.</h4> Stem cell and cell line assays are reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS4708' rel='noopener noreferrer' target='_blank'>MTBLS4708</a>.Xenograft assays are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS730' rel='noopener noreferrer' target='_blank'>MTBLS730</a>.

Project description:Glioblastoma (GBM) is a common and deadly form of brain tumor in adults. Dysregulated metabolism in GBM offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome, and the glycoproteome of human subgroup-specific GBM sphere-forming cells (GSC). L-fucose abundance and core fucosylation activation were elevated in mesenchymal (MES) compared with proneural GSCs; this pattern was retained in subgroup-specific xenografts and in subgroup-affiliated human patient samples. Genetic and pharmacological inhibition of core fucosylation significantly reduced tumor growth in MES GBM preclinical models. Liquid chromatography-mass spectrometry (LC-MS)-based glycoproteomic screening indicated that most MES-restricted core-fucosylated proteins are involved in therapeutically relevant GBM pathological processes, such as extracellular matrix interaction, cell adhesion, and integrin-mediated signaling. Selective L-fucose accumulation in MES GBMs was observed using preclinical minimally invasive PET, implicating this metabolite as a potential subgroup-restricted biomarker.Overall, these findings indicate that L-fucose pathway activation in MES GBM is a subgroup-specific dependency that could provide diagnostic markers and actionable therapeutic targets.<h4>SIGNIFICANCE: Metabolic characterization of subgroup-specific glioblastoma (GBM) sphere-forming cells identifies the L-fucose pathway as a vulnerability restricted to mesenchymal GBM, disclosing a potential precision medicine strategy for targeting cancer metabolism.</h4> Xenograft assays are reported in the current study MTBLS730.Stem cell and cell line assays are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS4708' rel='noopener noreferrer' target='_blank'>MTBLS4708</a>.

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A gel-top model for characterizing the mesenchymal features of glioblastoma cells

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