Metabolic Dependencies in Medulloblastoma Reflect Underlying Cellular Origins

Medulloblastoma (MB) is the most common malignant brain tumour of childhood and comprises molecularly and clinically distinct subgroups arising from defined neuronal progenitor populations. 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. This metabolic configuration mirrors neuronal bioenergetics and reflects suppressed glycolytic capacity rather than oncogene-driven reprogramming. Consistent with this rigidity, MB cells fail to compensate for mitochondrial inhibition by upregulating glycolysis and are exquisitely sensitive to pharmacologic complex I blockade. In orthotopic patient-derived xenograft models, complex I inhibitors including IACS-010759 and metformin significantly extend survival across high-risk MB subgroups. Together, these findings establish oxidative phosphorylation as a lineage-constrained metabolic vulnerability in MB and provide a strong rationale for therapeutic targeting of mitochondrial respiration in this disease.