Lipid metabolism as a therapeutic vulnerability in medulloblastoma

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children and presents a varied prognosis, with some patients succumbing to the disease and survivors presenting neurotoxic sequelae from treatment. Reprogramming of cellular metabolism is one of the hallmarks of cancer, therefore, in the current study we focussed on investigating the lipidomic profile of MB to identify novel therapeutic strategies. We identified an increase of unsaturated fatty acids in MB compared to human neural stem cells, that resulted in the identification of Stearoyl-CoA desaturase 1 (SCD1) as a potential therapeutic target in MB. RNA sequencing of cells treated with SCD1 inhibitor resulted in the activation of several interconnected pathways that regulate apoptosis, proliferation, differentiation, inflammation, and metabolic homeostasis. Moreover, microarray expression data from a cohort of 763 pediatric MB patient samples was investigated, identifying that SCD expression is a prognostic marker in Group 3 and Group 4 MB subgroups. In addition, we identified that Group 3 and Group 4 MB patient samples with very high SCD expression may be enriched in cholesterol homeostasis and specific amino acid metabolic pathways (glycerine, serine, and threonine), while those with very low SCD expression were enriched in purine nucleotide metabolism. Finally, we propose potential combinatorial or synergistic therapies with SCD1 inhibition to avoid potential resistance, including the use of beta-blockers, NF-KB inhibitors, or statins.