Single-cell multi-omics analysis 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, single nuclei multiome analysis of matched primary and recurrent tumors was performed in this study. A persistent progenitor population supporting resistance to therapy was identified. Additionally, distinct chromatin landscapes are linked to altered transcription and correspond to metabolic reprogramming. modeling of radiation resistance resolves 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 novel target pathways for MYC-driven medulloblastoma.