Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma PMID: 32445698

ADC Targets in Oncology

2026-04-10

Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

Cell. 2020 Jun 11;181(6):1329-1345.e24. doi: 10.1016/j.cell.2020.04.047.

Kulandaimanuvel Antony Michealraj ¹ , Sachin A Kumar ² , Leo J Y Kim ³ , Florence M G Cavalli ¹ , David Przelicki ² , John B Wojcik ⁴ , Alberto Delaidelli ⁵ , Andrea Bajic ⁶ , Olivier Saulnier ¹ , Graham MacLeod ⁷ , Ravi N Vellanki ⁸ , Maria C Vladoiu ² , Paul Guilhamon ¹ , Winnie Ong ² , John J Y Lee ² , Yanqing Jiang ¹ , Borja L Holgado ¹ , Alex Rasnitsyn ⁹ , Ahmad A Malik ¹⁰ , Ricky Tsai ¹¹ , Cory M Richman ⁹ , Kyle Juraschka ² , Joonas Haapasalo ¹ , Evan Y Wang ⁹ , Pasqualino De Antonellis ¹ , Hiromichi Suzuki ¹ , Hamza Farooq ¹ , Polina Balin ² , Kaitlin Kharas ² , Randy Van Ommeren ² , Olga Sirbu ⁹ , Avesta Rastan ¹ , Stacey L Krumholtz ¹ , Michelle Ly ² , Moloud Ahmadi ⁷ , Geneviève Deblois ⁸ , Dilakshan Srikanthan ² , Betty Luu ¹ , James Loukides ¹ , Xiaochong Wu ¹ , Livia Garzia ¹² , Vijay Ramaswamy ¹³ , Evgeny Kanshin ¹⁴ , María Sánchez-Osuna ¹⁴ , Ibrahim El-Hamamy ¹⁵ , Fiona J Coutinho ¹ , Panagiotis Prinos ¹⁶ , Sheila Singh ¹⁷ , Laura K Donovan ¹ , Craig Daniels ¹ , Daniel Schramek ¹⁰ , Mike Tyers ¹⁴ , Samuel Weiss ¹⁸ , Lincoln D Stein ¹⁵ , Mathieu Lupien ⁸ , Bradly G Wouters ⁸ , Benjamin A Garcia ⁴ , Cheryl H Arrowsmith ¹⁹ , Poul H Sorensen ⁵ , Stephane Angers ²⁰ , Nada Jabado ²¹ , Peter B Dirks ²² , Stephen C Mack ²³ , Sameer Agnihotri ²⁴ , Jeremy N Rich ²⁵ , Michael D Taylor ²⁶

Affiliations

1. The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
2. The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada.
3. Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
4. Department of Biochemistry and Biophysics and Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5. Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V6T 1Z2, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z2, Canada.
6. Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
7. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
8. Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
9. The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
10. Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
11. Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
12. Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada.
13. The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
14. Institute for Research in Immunology and Cancer (IRIC), Department of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
15. Computational Biology Program, Adaptive Oncology Theme, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
16. Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto, ON M5G 1L7, Canada.
17. Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada.
18. Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
19. Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto, ON M5G 1L7, Canada.
20. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada; Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
21. Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.
22. The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
23. Texas Children's Hospital Cancer Center, Department of Pediatrics, Baylor College of Medicine, Dan L. Duncan Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].
24. Department of Neurological Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: [email protected].
25. Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address: [email protected].
26. The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada. Electronic address: [email protected].

Abstract

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike Other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

Keywords

cancer metabolism; ependymoma; epigenetics; hindbrain development; microenvironment; paediatric cancer.