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

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 (GSCs). L-fucose abundance and core fucosylation activation were elevated in mesenchymal (MES) compared to proneural (PN) 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 pre-clinical minimally-invasive positron emission tomography (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.

Targeting Post-Translational Modifications to Improve Combinatorial Therapies in Breast Cancer: The Role of Fucosylation

“…Core-fucosylation is the most common form of fucosylation and has been associated with inflammation and cancer aggressiveness [ 9 ]. In particular, core-fucosylation has been related to inferior prognosis, as well as to increased proliferation, metastatic potential, and therapy resistance in melanoma [ 10 ], hepatocellular carcinoma [ 11 ], lung cancer [ 12 , 13 , 14 ], prostate cancer [ 15 , 16 ], pancreatic ductal adenocarcinoma [ 17 ], glioblastoma [ 18 ] and breast cancer [ 19 , 20 ].…”

“…According to the findings on EMT in NSCLC, also PMT in GBM has been recently associated with the increase in FUT8 expression and core-fucosylation, in parallel with significantly faster tumor growth and matrix invasion. When tested on patient-derived tissues, FUT8 protein, and core-fucosylation resulted mostly upregulated in the restricted subset of mesenchymal-like GBM, and it was associated with dismal prognosis [ 18 ].…”

“…More in detail, exon 1 encodes only for 5′ Untranslated Regions (UTR) sequences containing potential binding sites for transcription factors (i.e., TATA-box, cMyb, GATA-1, bHLH) [ 39 ]. Of note, a positive transcriptional axis has been recognized in melanoma with Transforming Growth Factor-β (TGF-β)-Induced Factor homeobox 2 (TGIF2) [ 10 ], whereas a negative one has been depicted with the transcription factor ASCL1 in small cell lung cancer [ 40 ] and glioblastoma [ 18 ]. Information on the relevance of TGIF2 and ASCL1 in FUT8 regulation in breast cancer is still lacking [ 10 , 40 ].…”

“…RNAi silencing of FUT8 has been shown to reduce core-fucosylation of cancer cells and functionally inhibit their migration and invasion in vitro [ 10 , 18 ], as well as tumor growth capacity in vivo [ 18 ]. To provide patients with feasible treatment protocols, genetic engineering strategies cannot be directly translated into clinics, and a handy drug is needed.…”

“…In line with those findings, Pieri et al examined the role of core-fucosylation in the mesenchymal subgroup of glioblastoma (GBM), the one associated with worse prognosis and chemoradiation resistance [ 18 ]. In orthotopic xenografts of human GBM, 2FF delivered intratumorally via micro-infusion pumps resulted in significantly reduced tumor volume and increased survival.…”