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Steroid-dependent metabolic rewiring reveals novel therapeutic and imaging approaches for glioblastoma

ABSTRACT: Steroid anti-inflammatory drugs, such as dexamethasone are routinely used to manage brain tumour-associated oedema, yet their impact on brain tumour metabolism remained largely unexplored. Here, a metabolomic screen in naive glioblastoma cells treated with dexamethasone revealed the accumulation of N1-methylnicotinamide, a product of N-methyltransferase (NNMT), through the activation of the glucocorticoid receptor. Using stable isotope-assisted metabolomics in glioblastoma patients we showed that nicotinamide flux into N1-methylnicotinamide exceeds that into NAD+, leading to a ~7 fold accumulation of N1-methylnicotinamide in tumour compared to surrounding brain tissue. In orthotopic mouse models, NNMT activity was enhanced by dexamethasone selectively in glioblastoma tumours but not in the contralateral brain. Leveraging the tumour-specific activity of NNMT and the NNMT-dependent trapping of nicotinamide, we developed a novel 11C-nicotinamide-based positron emission tomography (PET) approach to visualize glioblastoma tumours in vivo. Furthermore, our findings demonstrate that the dexamethasone-induced methionine-dependent methylation of nicotinamide becomes detrimental for glioblastoma growth when combined with a methionine-restricted diet. These results show that steroids rewire methionine and nicotinamide metabolism, enabling the development of innovative PET imaging and metabolic therapies for glioblastoma patients.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Saverio Tardito David Sumpton Maria Francesca Allega

PROVIDER: MSV000096560 | MassIVE | Fri Nov 29 02:36:00 GMT 2024

REPOSITORIES: MassIVE

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