Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

Derek Dang¹, Akash Deogharkar¹, John McKolay¹, Kyle S Smith², Pooja Panwalkar¹, Simon Hoffman¹, Wentao Tian¹, Sunjong Ji³, Ana P Azambuja⁴, Siva Kumar Natarajan¹, Joanna Lum¹, Jill Bayliss¹, Katie Manzeck¹, Stefan R Sweha⁵, Erin Hamanishi¹, Matthew Pun¹, Diya Patel¹, Sagar Rau¹, Olamide Animasahun⁶, Abhinav Achreja⁷, Martin P Ogrodzinski⁸, Jutta Diessl⁹, Jennifer Cotter¹⁰, Debra Hawes¹⁰, Fusheng Yang¹⁰, Robert Doherty³, Andrea T Franson³, Allison R Hanaford¹¹, Charles G Eberhart¹², Eric H Raabe¹³, Brent A Orr¹⁴, Robert J Wechsler-Reya¹⁵, Brandon Chen¹⁶, Costas A Lyssiotis¹⁷, Yatrik M Shah¹⁷, Sophia Y Lunt¹⁸, Ruma Banerjee⁹, Alexander R Judkins¹⁰, John R Prensner¹⁹, Carl Koschmann¹⁹, Sebastian M Waszak²⁰, Deepak Nagrath²¹, Marcos Simoes-Costa⁴, Paul A Northcott², Sriram Venneti²²

Affiliations

¹ Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
² Department of Developmental Neurobiology, Neurobiology and Brain Tumor Program, St. Jude Children's Research Hospital, Memphis, TN, USA; Center of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
³ Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA.
⁴ Department of Pathology, Boston Children's Hospital, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
⁵ Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA; Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
⁷ Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.
⁹ Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
¹⁰ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹¹ Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Division of Neuropathology, Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹² Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Division of Neuropathology, Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹³ Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Division of Pediatric Oncology, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Division of Neuropathology, Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁵ Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
¹⁶ Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁷ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁸ Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA; Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI, USA.
¹⁹ Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
²⁰ Laboratory of Computational Neuro-Oncology, Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
²¹ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA; Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
²² Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. Electronic address: svenneti@med.umich.edu.

PMID: 40378837
PMCID: PMC12151749 (available on 2026-06-09)
DOI: 10.1016/j.ccell.2025.04.013

Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

Derek Dang et al. Cancer Cell. 2025.

. 2025 Jun 9;43(6):1159-1174.e8.

doi: 10.1016/j.ccell.2025.04.013. Epub 2025 May 15.

Authors

Affiliations

¹ Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
² Department of Developmental Neurobiology, Neurobiology and Brain Tumor Program, St. Jude Children's Research Hospital, Memphis, TN, USA; Center of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
³ Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA.
⁴ Department of Pathology, Boston Children's Hospital, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
⁵ Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA; Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
⁷ Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.
⁹ Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
¹⁰ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹¹ Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Division of Neuropathology, Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹² Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Division of Neuropathology, Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹³ Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Division of Pediatric Oncology, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Division of Neuropathology, Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁵ Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
¹⁶ Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁷ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁸ Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA; Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI, USA.
¹⁹ Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
²⁰ Laboratory of Computational Neuro-Oncology, Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
²¹ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA; Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
²² Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. Electronic address: svenneti@med.umich.edu.

PMID: 40378837
PMCID: PMC12151749 (available on 2026-06-09)
DOI: 10.1016/j.ccell.2025.04.013

Abstract

MYC-driven group-3 medulloblastomas (MBs) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identify upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of group-3 MB with poor prognosis. DLAT is induced by c-MYC and targeting DLAT lowers TCA cycle metabolism and glutathione synthesis. We also note upregulation of isocitrate dehydrogenase 1 (IDH1) gene expression in group-3 MB patient tumors and suppression of IDH1 epigenetically reduces c-MYC and downstream DLAT levels in multiple c-MYC amplified cancers. DLAT is a central regulator of cuproptosis (copper-dependent cell death) induced by the copper ionophore elesclomol. DLAT expression in group-3 MB cells correlates with increased sensitivity to cuproptosis. Elesclomol is brain-penetrant and suppresses tumor growth in vivo in multiple group-3 MB animal models. Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill group-3 MB by cuproptosis.

Keywords: cancer metabolism; cell death; copper; cuproptosis; elesclomol; epigenetics; pediatric brain tumor; protein lipoylation.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Northcott PA, Robinson GW, Kratz CP, Mabbott DJ, Pomeroy SL, Clifford SC, Rutkowski S, Ellison DW, Malkin D, Taylor MD, et al. (2019). Medulloblastoma. Nat. Rev. Dis. Primer 5, 11. 10.1038/s41572-019-0063-6. - DOI - PubMed
1. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, et al. (2021). The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncol. 23, 1231–1251. 10.1093/neuonc/noab106. - DOI - PMC - PubMed
1. Gajjar AJ, and Robinson GW (2014). Medulloblastoma-translating discoveries from the bench to the bedside. Nat. Rev. Clin. Oncol 11, 714–722. 10.1038/nrclinonc.2014.181. - DOI - PubMed
1. Gajjar A, Pfister SM, Taylor MD, and Gilbertson RJ (2014). Molecular insights into pediatric brain tumors have the potential to transform therapy. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res 20, 5630–5640. 10.1158/1078-0432.CCR-14-0833. - DOI - PMC - PubMed
1. Jackson K, and Packer RJ (2023). Recent Advances in Pediatric Medulloblastoma. Curr. Neurol. Neurosci. Rep 23, 841–848. 10.1007/s11910-023-01316-9. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

Affiliations

Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous