부산대학교 도서관

Keywords microenvironment; paediatric cancer; cancer metabolism; ependymoma; epigenetics; hindbrain development Highlights * Hypoxic microenvironment is essential for propagation and growth of PFA ependymoma * Hypoxia controls metabolic intermediates that maintain an H3K27 hypomethylated genome * Inhibition or potentiation of histone lysine methylation diminishes PFA survival * Gliogenic lineage of developing fetal hindbrain mirrors PFA metabolic alterations Summary 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. Author Affiliation: (1) The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada (2) Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada (3) Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada (4) Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA (5) Department of Biochemistry and Biophysics and Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA (6) Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V6T 1Z2, Canada (7) Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z2, Canada (8) Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada (9) Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada (10) Department of Medical Biophysics, 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) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada (13) Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada (14) Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada (15) Institute for Research in Immunology and Cancer (IRIC), Department of Medicine, Universite de Montreal, Montreal, QC H3C 3J7, Canada (16) Computational Biology Program, Adaptive Oncology Theme, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada (17) Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada (18) Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto, ON M5G 1L7, Canada (19) Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada (20) Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada (21) Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada (22) Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada (23) Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada (24) Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada (25) Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada (26) Texas Children's Hospital Cancer Center, Department of Pediatrics, Baylor College of Medicine, Dan L. Duncan Cancer Center, Houston, TX 77030, USA (27) Department of Neurological Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA * Corresponding author Article History: Received 27 September 2019; Revised 16 March 2020; Accepted 24 April 2020 (miscellaneous) Published: May 22, 2020 (footnote)28 These authors contributed equally (footnote)29 Lead Contact Byline: Kulandaimanuvel Antony Michealraj (1,2,28), Sachin A. Kumar (1,2,3,28), Leo J.Y. Kim (4,28), Florence M.G. Cavalli (1,2), David Przelicki (1,2,3), John B. Wojcik (5), Alberto Delaidelli (6,7), Andrea Bajic (8), Olivier Saulnier (1,2), Graham MacLeod (9), Ravi N. Vellanki (12), Maria C. Vladoiu (1,2,3), Paul Guilhamon (1,2), Winnie Ong (1,2,3), John J.Y. Lee (1,2,3), Yanqing Jiang (1,2), Borja L. Holgado (1,2), Alex Rasnitsyn (1,2,10), Ahmad A. Malik (11,17), Ricky Tsai (11), Cory M. Richman (1,2,10), Kyle Juraschka (1,2,3), Joonas Haapasalo (1,2), Evan Y. Wang (1,2,10), Pasqualino De Antonellis (1,2), Hiromichi Suzuki (1,2), Hamza Farooq (1,2), Polina Balin (1,2,3), Kaitlin Kharas (1,2,3), Randy Van Ommeren (1,2,3), Olga Sirbu (1,2,10), Avesta Rastan (1,2), Stacey L. Krumholtz (1,2), Michelle Ly (1,2,3), Moloud Ahmadi (9), Genevieve Deblois (12), Dilakshan Srikanthan (1,2,3), Betty Luu (1,2), James Loukides (1,2), Xiaochong Wu (1,2), Livia Garzia (13), Vijay Ramaswamy (1,14), Evgeny Kanshin (15), Maria Sanchez-Osuna (15), Ibrahim El-Hamamy (16,17), Fiona J. Coutinho (1,2), Panagiotis Prinos (18), Sheila Singh (19,20,21), Laura K. Donovan (1,2), Craig Daniels (1,2), Daniel Schramek (11,17), Mike Tyers (15), Samuel Weiss (22), Lincoln D. Stein (16,17), Mathieu Lupien (12), Bradly G. Wouters (12), Benjamin A. Garcia (5), Cheryl H. Arrowsmith (10,12,18), Poul H. Sorensen (6,7), Stephane Angers (9,23), Nada Jabado (8,24), Peter B. Dirks (1,2,17,25), Stephen C. Mack [stephen.mack@bcm.edu] (26,*), Sameer Agnihotri [sameer.agnihotri@gmail.com] (27,**), Jeremy N. Rich [drjeremyrich@gmail.com] (4,***), Michael D. Taylor [mdt.cns@gmail.com] (1,2,3,10,25,29,****)