Lipidomic analysis of isolated lipid droplets reveals potential metabolic pathway differences between medulloblastoma...

Medulloblastomas (MBs) are a highly aggressive paediatric brain tumour which is very difficult to treat. Lipid metabolism has emerged as a crucial determinant of tumour progression, metastasis and therapy resistance in MBs. Lipid droplets (LDs) are lipid-rich organelles that store neutral lipids; their biology and function remain poorly characterised within MBs.

MB cells from the low-aggressive Sonic hedgehog (SHH) subgroup (DAOY, UW228-2) and the high-aggressive group 3 (G4) and group 4 (G4) subgroups (D458, D283) were treated with 80 μM oleic acid (OA), 50 μM cholesterol (Chol) or a mix to induce LD formation. LDs were isolated, and lipidomic analysis was performed.

No lipid species were consistently upregulated across all cell lines under any treatment condition. SHH cell lines exhibited a broad and consistent lipidomic response across all three treatments, resulting in a pronounced triacylglyceride (TAG) and cholesterol ester (CE) storage profile. The more aggressive subgroups exhibited a more selective, OA-driven phenotype, characterised by longer-chain TAG and CE species. Across all cell lines, OA produced the strongest LD expansion and metabolic separation, whereas Chol elicited a more restricted but highly subgroup-specific signature. G3/G4 Chol responses provide evidence for lipid metabolism rewiring, which could be responsible for the more aggressive phenotype.

These findings demonstrate that MB subtypes not only exhibit distinct basal lipid signatures but also engage in fundamentally different lipid remodelling in response to FA overload. These distinct lipid-handling signatures display metabolic heterogeneity across MB subgroups and suggest subtype-specific vulnerabilities. Overall, these findings position LD remodelling as a potential metabolic target of MB cells.