Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

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

doi:10.1016/j.cell.2020.04.047

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. Epub 2020 May 22.

Authors

Kulandaimanuvel Antony Michealraj¹, Sachin A Kumar², Leo J Y Kim³, Florence M G Cavalli¹, David Przelicki², John B Wojcik⁴, Alberto Delaidelli⁵, Andrea Bajic⁶, Olivier Saulnier¹, Graham MacLeod⁷, Ravi N Vellanki⁸, Maria C Vladoiu², Paul Guilhamon¹, Winnie Ong², John J Y Lee², Yanqing Jiang¹, Borja L Holgado¹, Alex Rasnitsyn⁹, Ahmad A Malik¹⁰, Ricky Tsai¹¹, Cory M Richman⁹, Kyle Juraschka², Joonas Haapasalo¹, Evan Y Wang⁹, Pasqualino De Antonellis¹, Hiromichi Suzuki¹, Hamza Farooq¹, Polina Balin², Kaitlin Kharas², Randy Van Ommeren², Olga Sirbu⁹, Avesta Rastan¹, Stacey L Krumholtz¹, Michelle Ly², Moloud Ahmadi⁷, Geneviève Deblois⁸, Dilakshan Srikanthan², Betty Luu¹, James Loukides¹, Xiaochong Wu¹, Livia Garzia¹², Vijay Ramaswamy¹³, Evgeny Kanshin¹⁴, María Sánchez-Osuna¹⁴, Ibrahim El-Hamamy¹⁵, Fiona J Coutinho¹, Panagiotis Prinos¹⁶, Sheila Singh¹⁷, Laura K Donovan¹, Craig Daniels¹, Daniel Schramek¹⁰, Mike Tyers¹⁴, Samuel Weiss¹⁸, Lincoln D Stein¹⁵, Mathieu Lupien⁸, Bradly G Wouters⁸, Benjamin A Garcia⁴, Cheryl H Arrowsmith¹⁹, Poul H Sorensen⁵, Stephane Angers²⁰, Nada Jabado²¹, Peter B Dirks²², Stephen C Mack²³, Sameer Agnihotri²⁴, Jeremy N Rich²⁵, Michael D Taylor²⁶

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: stephen.mack@bcm.edu.
²⁴ Department of Neurological Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: sameer.agnihotri@gmail.com.
²⁵ Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address: drjeremyrich@gmail.com.
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: mdt.cns@gmail.com.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Neoplasms / genetics
Brain Neoplasms / metabolism
Cell Line
Cell Proliferation / genetics
DNA Methylation / genetics
Ependymoma / genetics*
Ependymoma / metabolism*
Epigenome / genetics*
Epigenomics / methods
Histones / genetics
Histones / metabolism
Humans
Infant
Infratentorial Neoplasms / genetics*
Infratentorial Neoplasms / metabolism*
Lysine / genetics
Lysine / metabolism
Male
Mice, Inbred C57BL
Mutation / genetics

Substances

Histones
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding