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.
Derek Dang  1 ,  Akash Deogharkar  1 ,  John McKolay  1 ,  Kyle S Smith  2 ,  Pooja Panwalkar  1 ,  Simon Hoffman  1 ,  Wentao Tian  1 ,  Sunjong Ji  3 ,  Ana P Azambuja  4 ,  Siva Kumar Natarajan  1 ,  Joanna Lum  1 ,  Jill Bayliss  1 ,  Katie Manzeck  1 ,  Stefan R Sweha  5 ,  Erin Hamanishi  1 ,  Matthew Pun  1 ,  Diya Patel  1 ,  Sagar Rau  1 ,  Olamide Animasahun  6 ,  Abhinav Achreja  7 ,  Martin P Ogrodzinski  8 ,  Jutta Diessl  9 ,  Jennifer Cotter  10 ,  Debra Hawes  10 ,  Fusheng Yang  10 ,  Robert Doherty  3 ,  Andrea T Franson  3 ,  Allison R Hanaford  11 ,  Charles G Eberhart  12 ,  Eric H Raabe  13 ,  Brent A Orr  14 ,  Robert J Wechsler-Reya  15 ,  Brandon Chen  16 ,  Costas A Lyssiotis  17 ,  Yatrik M Shah  17 ,  Sophia Y Lunt  18 ,  Ruma Banerjee  9 ,  Alexander R Judkins  10 ,  John R Prensner  19 ,  Carl Koschmann  19 ,  Sebastian M Waszak  20 ,  Deepak Nagrath  21 ,  Marcos Simoes-Costa  4 ,  Paul A Northcott  2 ,  Sriram Venneti  22
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: [email protected].
PMID: 40378837 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.
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