2. Academic Validation
  3. ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression

ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression

  • Nature. 2026 Apr;652(8111):1004-1015. doi: 10.1038/s41586-025-10005-1.
Siva Kumar Natarajan 1 2 3,  Joanna Lum 1 2 3,  James Haggerty Skeans 1 2 4,  Minal Nenwani 5 6 7,  Sanjana Eyunni 3 8,  Mateus Mota 1 2,  Jill M Bayliss 1 2,  Akash Deogharkar 1 2,  Erin Taya Hamanishi 1 9,  Matthew Pun 1 2 4,  Stefan R Sweha 1 2,  Simon Hoffman 1 2,  Eleanor Young 8,  Qiuyang Zhang 10 11,  Rijul Mehta 1 2,  Olamide Animasahun 5 6 12,  Pranav Narayanan 1 2,  Sushanth Sunil 1 2,  Abhijit Parolia 8 10 11,  Peter Sajjakulnukit 13,  Pooja Panwalkar 1 2,  Robert Doherty 9,  Madison Clausen 9,  Derek Dang 1 2 3,  Debra Hawes 14,  Fusheng Yang 14,  Mariarita Santi 15,  Alexander R Judkins 14,  Yelena Wilson 16,  Thomas Vigil 13,  Andrea Franson 9,  Richard M Mortensen 17,  Tatsuya Ozawa 18 19,  Andrea Griesinger 20 21,  Eric C Holland 18 19,  Nicholas K Foreman 20 21,  Kulandaimanuvel Antony Michealraj 22,  Sameer Agnihotri 23 24 25,  Michael Taylor 26,  Richard J Gilbertson 27 28,  Carl Koschmann 9 10,  Arul M Chinnaiyan 8 10 11 29,  Costas A Lyssiotis 10 13 30,  Deepak Nagrath 5 6 7 10 12,  Sriram Venneti 31 32 33 34
Affiliations

Affiliations

  • 1 Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 2 Chad Carr Pediatric Brain Tumor Center, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
  • 3 Molecular and Cellular Pathology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 4 Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 5 Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA.
  • 6 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 7 Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
  • 8 Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 9 Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
  • 10 Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 11 Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 12 Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 13 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • 14 Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine University of Southern California, Los Angeles, CA, USA.
  • 15 Anatomic Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 16 Department of Pathology, Akron Children's Hospital, Akron, OH, USA.
  • 17 Departments of Molecular and Integrative Physiology, Internal Medicine, and Pharmacology, University of Michigan, Ann Arbor, MI, USA.
  • 18 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 19 Seattle Tumor Translational Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 20 Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • 21 Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA.
  • 22 Department of Neurosurgery, University of Pittsburgh School of Medicine and Cancer 97 Biology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
  • 23 Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 24 John G. Rangos Sr Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • 25 Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 26 Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.
  • 27 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • 28 Department of Oncology, University of Cambridge, Cambridge, UK.
  • 29 Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 30 Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.
  • 31 Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. [email protected].
  • 32 Chad Carr Pediatric Brain Tumor Center, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 33 Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. [email protected].
  • 34 Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. [email protected].
PMID: 41639460 DOI: 10.1038/s41586-025-10005-1
Abstract

ZFTA-RELA+ ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA1. Here we show that ZFTA-RELA+ cells produce itaconate, a key macrophage-associated immunomodulatory metabolite2. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA-RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA-RELA levels. Itaconate epigenetically activates ZFTA-RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA-RELA+ tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA-RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA-RELA epigenetically suppresses PTEN expression to upregulate PI3K-mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K-mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA-RELA+ ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA+ ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.

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