2. Academic Validation
  3. Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

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

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 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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