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

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 journal › Article › peer-review

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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 language	English
Pages (from-to)	1329-1345.e24
Journal	Cell
Volume	181
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2020.04.047
State	Published - Jun 11 2020

Keywords

cancer metabolism
ependymoma
epigenetics
hindbrain development
microenvironment
paediatric cancer

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10.1016/j.cell.2020.04.047

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Michealraj, K. A., Kumar, S. A., Kim, L. J. Y., Cavalli, F. M. G., Przelicki, D., Wojcik, J. B., Delaidelli, A., Bajic, A., Saulnier, O., MacLeod, G., Vellanki, R. N., Vladoiu, M. C., Guilhamon, P., Ong, W., Lee, J. J. Y., Jiang, Y., Holgado, B. L., Rasnitsyn, A., Malik, A. A., ... Taylor, M. D. (2020). Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma. Cell, 181(6), 1329-1345.e24. https://doi.org/10.1016/j.cell.2020.04.047

@article{6e100d5c972647c5876517d5dddad144,

title = "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. Hypoxia reprograms the cellular metabolome and epigenome to promote growth of the most lethal ependymomas.",

keywords = "cancer metabolism, ependymoma, epigenetics, hindbrain development, microenvironment, paediatric cancer",

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

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = jun,

day = "11",

doi = "10.1016/j.cell.2020.04.047",

language = "English",

volume = "181",

pages = "1329--1345.e24",

journal = "Cell",

issn = "0092-8674",

number = "6",

}

Michealraj, KA, Kumar, SA, Kim, LJY, Cavalli, FMG, Przelicki, D, Wojcik, JB, Delaidelli, A, Bajic, A, Saulnier, O, MacLeod, G, Vellanki, RN, Vladoiu, MC, Guilhamon, P, Ong, W, Lee, JJY, Jiang, Y, Holgado, BL, Rasnitsyn, A, Malik, AA, Tsai, R, Richman, CM, Juraschka, K, Haapasalo, J, Wang, EY, De Antonellis, P, Suzuki, H, Farooq, H, Balin, P, Kharas, K, Van Ommeren, R, Sirbu, O, Rastan, A, Krumholtz, SL, Ly, M, Ahmadi, M, Deblois, G, Srikanthan, D, Luu, B, Loukides, J, Wu, X, Garzia, L, Ramaswamy, V, Kanshin, E, Sánchez-Osuna, M, El-Hamamy, I, Coutinho, FJ, Prinos, P, Singh, S, Donovan, LK, Daniels, C, Schramek, D, Tyers, M, Weiss, S, Stein, LD, Lupien, M, Wouters, BG, Garcia, BA, Arrowsmith, CH, Sorensen, PH, Angers, S, Jabado, N, Dirks, PB, Mack, SC, Agnihotri, S, Rich, JN & Taylor, MD 2020, 'Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma', Cell, vol. 181, no. 6, pp. 1329-1345.e24. https://doi.org/10.1016/j.cell.2020.04.047

TY - JOUR

T1 - Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

AU - Michealraj, Kulandaimanuvel Antony

AU - Kumar, Sachin A.

AU - Kim, Leo J.Y.

AU - Cavalli, Florence M.G.

AU - Przelicki, David

AU - Wojcik, John B.

AU - Delaidelli, Alberto

AU - Bajic, Andrea

AU - Saulnier, Olivier

AU - MacLeod, Graham

AU - Vellanki, Ravi N.

AU - Vladoiu, Maria C.

AU - Guilhamon, Paul

AU - Ong, Winnie

AU - Lee, John J.Y.

AU - Jiang, Yanqing

AU - Holgado, Borja L.

AU - Rasnitsyn, Alex

AU - Malik, Ahmad A.

AU - Tsai, Ricky

AU - Richman, Cory M.

AU - Juraschka, Kyle

AU - Haapasalo, Joonas

AU - Wang, Evan Y.

AU - De Antonellis, Pasqualino

AU - Suzuki, Hiromichi

AU - Farooq, Hamza

AU - Balin, Polina

AU - Kharas, Kaitlin

AU - Van Ommeren, Randy

AU - Sirbu, Olga

AU - Rastan, Avesta

AU - Krumholtz, Stacey L.

AU - Ly, Michelle

AU - Ahmadi, Moloud

AU - Deblois, Geneviève

AU - Srikanthan, Dilakshan

AU - Luu, Betty

AU - Loukides, James

AU - Wu, Xiaochong

AU - Garzia, Livia

AU - Ramaswamy, Vijay

AU - Kanshin, Evgeny

AU - Sánchez-Osuna, María

AU - El-Hamamy, Ibrahim

AU - Coutinho, Fiona J.

AU - Prinos, Panagiotis

AU - Singh, Sheila

AU - Donovan, Laura K.

AU - Daniels, Craig

AU - Schramek, Daniel

AU - Tyers, Mike

AU - Weiss, Samuel

AU - Stein, Lincoln D.

AU - Lupien, Mathieu

AU - Wouters, Bradly G.

AU - Garcia, Benjamin A.

AU - Arrowsmith, Cheryl H.

AU - Sorensen, Poul H.

AU - Angers, Stephane

AU - Jabado, Nada

AU - Dirks, Peter B.

AU - Mack, Stephen C.

AU - Agnihotri, Sameer

AU - Rich, Jeremy N.

AU - Taylor, Michael D.

PY - 2020/6/11

Y1 - 2020/6/11

N2 - 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.

AB - 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.

KW - cancer metabolism

KW - ependymoma

KW - epigenetics

KW - hindbrain development

KW - microenvironment

KW - paediatric cancer

UR - http://www.scopus.com/inward/record.url?scp=85085759955&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2020.04.047

DO - 10.1016/j.cell.2020.04.047

M3 - Article

C2 - 32445698

AN - SCOPUS:85085759955

SN - 0092-8674

VL - 181

SP - 1329-1345.e24

JO - Cell

JF - Cell

IS - 6

ER -

Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

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