Abstract Background Medulloblastoma (MB) is the most prevalent malignant pediatric brain tumor, characterized by significant molecular diversity. Among its subgroups, Group 3 (G3) MB, frequently driven by the MYC oncogene, is associated with the poorest clinical outcomes. While transcriptional exploration of MB tumors has been extensively performed, the limited availability of metabolomic data has constrained understanding of the core biological processes sustaining tumor aggressiveness. Methods We performed an extensive characterization of primary MB samples using a multi-omic integration approach comprising proteomics and metabolomics. Key findings were validated using cutting-edge technologies, including untargeted lipidomics, MALDI-MSI, and Transmission Electron Microscopy (TEM), on flash-frozen samples and Patient-Derived Xenografts (PDXs). Using an extensive combination of cytofluorometry, imaging, cellular metabolism assays and orthotopic preclinical models, we functionally assessed the cellular phenotypes in-vitro and in-vivo. Results Integrated analyses uncovered pronounced metabolic heterogeneity across medulloblastoma, with G3 tumors displaying the greatest diversity. In a subset of MYC-high G3 tumors, we identified a lipid-dependent metabolic program characterized by enhanced de novo lipogenesis, triglyceride synthesis, and the accumulation of lipid droplets (LD). Mechanistically, we show that these cells exhibit a unique dependence on LD-mitochondria communication to fuel fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Functional perturbation of lipid droplet biogenesis through inhibition of diacylglycerol acyltransferase 1 (DGAT1) disrupted lipid compartmentation, increasing membrane-associated polyunsaturated fatty acids, and triggering ferroptotic cell death by lipid peroxidation. MYC-high G3 models showed heightened dependency on this pathway, and DGAT1 inhibition significantly impaired tumor growth and improved survival in vivo. Conclusions This study identifies lipid droplets as both a necessary energy storage unit and critical metabolic defense mechanism in MYC-driven G3 medulloblastoma. Moreover, this work establishes the MYC-DGAT-lipid droplet axis as a targetable vulnerability, providing a strong rationale for metabolism-based precision therapies in high-risk pediatric brain tumors.
Bernardi et al. (Tue,) studied this question.