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Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

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.

SUBMITTER: Michealraj KA

PROVIDER: S-EPMC10782558 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

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

Cell 20200522 6

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). PF ...[more]

PMID: 32445698

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Project description:Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification.

Dataset Information

Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Publications

Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

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