Aberrant L-Fucose Accumulation and Increased Core Fucosylation Are Metabolic Liabilities in Mesenchymal Glioblastoma

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 ther-apeutic 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 gly-coproteome of human subgroup-specific GBM sphere-forming cells (GSC). L-fucose abundance and core fucosylation activa-tion 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 fuco-sylation 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 ther-apeutically relevant GBM pathological processes, such as extra -cellular 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 acti-vation in MES GBM is a subgroup-specific dependency that could provide diagnostic markers and actionable therapeutic targets.Significance: Metabolic characterization of subgroup-specific glio-blastoma (GBM) sphere-forming cells identifies the L-fucose pathway as a vulnerability restricted to mesenchymal GBM, disclosing a poten-tial precision medicine strategy for targeting cancer metabolism.