Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

Derek Dang; Akash Deogharkar; John McKolay; Kyle S Smith; Pooja Panwalkar; Simon Hoffman; Wentao Tian; Sunjong Ji; Ana P Azambuja; Siva Kumar Natarajan; Joanna Lum; Jill Bayliss; Katie Manzeck; Stefan R Sweha; Erin Hamanishi; Matthew Pun; Diya Patel; Sagar Rau; Olamide Animasahun; Abhinav Achreja; Martin P Ogrodzinski; Jutta Diessl; Jennifer Cotter; Debra Hawes; Fusheng Yang; Robert Doherty; Andrea T Franson; Allison R Hanaford; Charles G Eberhart; Eric H Raabe; Brent A Orr; Robert J Wechsler-Reya; Brandon Chen; Costas A Lyssiotis; Yatrik M Shah; Sophia Y Lunt; Ruma Banerjee; Alexander R Judkins; John R Prensner; Carl Koschmann; Sebastian M Waszak; Deepak Nagrath; Marcos Simoes-Costa; Paul A Northcott; Sriram Venneti

doi:10.1016/j.ccell.2025.04.013

Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

Cancer Cell. 2025 Jun 9;43(6):1159-1174.e8. doi: 10.1016/j.ccell.2025.04.013. Epub 2025 May 15.

Authors

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

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.

MeSH terms

Animals
Cell Line, Tumor
Cerebellar Neoplasms* / drug therapy
Cerebellar Neoplasms* / genetics
Cerebellar Neoplasms* / metabolism
Cerebellar Neoplasms* / pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Hydrazines / pharmacology
Isocitrate Dehydrogenase* / genetics
Isocitrate Dehydrogenase* / metabolism
Medulloblastoma* / drug therapy
Medulloblastoma* / enzymology
Medulloblastoma* / genetics
Medulloblastoma* / metabolism
Medulloblastoma* / pathology
Mice
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Xenograft Model Antitumor Assays

Substances

Isocitrate Dehydrogenase
IDH1 protein, human
Proto-Oncogene Proteins c-myc
MYC protein, human
Hydrazines

Abstract

MeSH terms

Substances

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