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 TsaiCory 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

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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. Hypoxia reprograms the cellular metabolome and epigenome to promote growth of the most lethal ependymomas.

Original languageEnglish
Pages (from-to)1329-1345.e24
JournalCell
Volume181
Issue number6
DOIs
StatePublished - Jun 11 2020

Keywords

  • cancer metabolism
  • ependymoma
  • epigenetics
  • hindbrain development
  • microenvironment
  • paediatric cancer

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