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

Bethany Veo (), Dong Wang, John DeSisto, Angela Pierce, Breauna Brunt, Pradeep Chandra Bompada, Andrew Donson, Andrew Goodspeed, Kiara Smart, Nicholas Foreman, Nathan Dahl and Rajeev Vibhakar ()
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Bethany Veo: University of Colorado Anschutz Medical Campus, Department of Pediatrics
Dong Wang: University of Colorado Anschutz Medical Campus, Department of Pediatrics
John DeSisto: University of Colorado Anschutz Medical Campus, Department of Pediatrics
Angela Pierce: University of Colorado Anschutz Medical Campus, Department of Pediatrics
Breauna Brunt: University of Colorado Anschutz Medical Campus, Department of Pediatrics
Pradeep Chandra Bompada: University of Colorado Anschutz Medical Campus, Department of Pediatrics
Andrew Donson: University of Colorado Anschutz Medical Campus, Department of Pediatrics
Andrew Goodspeed: University of Colorado Cancer Center
Kiara Smart: University of Colorado Anschutz Medical Campus, Department of Pediatrics
Nicholas Foreman: University of Colorado Anschutz Medical Campus, Department of Pediatrics
Nathan Dahl: University of Colorado Anschutz Medical Campus, Department of Pediatrics
Rajeev Vibhakar: University of Colorado Anschutz Medical Campus, Department of Pediatrics

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65466-9

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