Dataset Information

Aberrant L-Fucose accumulation and increased core fucosylation are metabolic liabilities in mesenchymal glioblastoma (Stem cell and cell line assays)

ABSTRACT:

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.

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.

Stem cell and cell line assays are reported in the current study MTBLS4708.

Xenograft assays are reported in MTBLS730.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - positive - reverse phase, Liquid Chromatography MS - negative - hilic

SUBMITTER: Denise Drago

PROVIDER: MTBLS4708 | MetaboLights | 2022-11-08

REPOSITORIES: MetaboLights

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	MTBLS4708	Other
	FILES	Other
	a_MTBLS4708_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS4708_LC-MS_negative_reverse-phase_metabolite_profiling-1.txt	Txt
	a_MTBLS4708_LC-MS_positive_hilic_metabolite_profiling.txt	Txt

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Publications

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

Pieri Valentina V Gallotti Alberto L AL Drago Denise D Cominelli Manuela M Pagano Ilaria I Conti Valentina V Valtorta Silvia S Coliva Angela A Lago Sara S Michelatti Daniela D Massimino Luca L Ungaro Federica F Perani Laura L Spinelli Antonello A Castellano Antonella A Falini Andrea A Zippo Alessio A Poliani Pietro L PL Moresco Rosa Maria RM Andolfo Annapaola A Galli Rossella R

Cancer research 20230101 2

PMID: 36409826

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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> 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>.