Metabolic Dependencies in Medulloblastoma Reflect Underlying Cellular Origins

Despite extensive genomic characterization, therapeutic strategies have remained largely unchanged for decades, and outcomes for high-risk disease remain poor. Here, we identify a conserved and lineage-encoded metabolic dependency that distinguishes MB from other brain tumours.

Using genome-wide CRISPR–Cas9 dropout screens across SHH, TP53-mutant SHH, and MYC-amplified Group 3 MB models, we uncover mitochondrial respiration as a core fitness requirement shared across subgroups. Unbiased metabolomic profiling of primary patient tumours reveals that MB occupies a distinct metabolic state characterized by depletion of glycolytic intermediates relative to ependymoma and glioma, independent of subgroup or MYC status.