Single-cell multi-omics identifies metabolism-linked epigenetic reprogramming as a driver of therapy-resistant medulloblastoma.

Medulloblastoma (MB) is the most prevalent malignant brain tumor in children, exhibiting clinical and genomic heterogeneity. Of the four major subgroups, Group 3 tumors (MYC-MB), display high levels of MYC and metastasis rates. Despite treatment with surgery, radiation, and chemotherapy, patients with Group 3 MB are more likely to develop aggressive recurrent tumors with poor survival. To examine resistance mechanisms in this study, we perform single nuclei multiome analysis of matched primary and recurrent tumors. Therapy resistant Medulloblastoma demonstrates an expanded persistent progenitor population. Additionally, distinct chromatin landscapes link to altered transcription and correspond with metabolic reprogramming. In vivo modeling of radiation resistance exhibits similar chromatin-based metabolic reprogramming focused on wild-type isocitrate dehydrogenase (IDH1) activity. IDH1 inhibition reverses resistance-mediated chromatin changes and enables radiation re-sensitization. Ultimately, these findings demonstrate the efficacy of single-cell multiome analysis in elucidating resistance mechanisms and identifying targetable pathways for MYC-driven medulloblastoma.