Glioma

REVIEW
Year
: 2021  |  Volume : 4  |  Issue : 4  |  Page : 85--91

Pediatric posterior fossa ependymoma and metabolism: A narrative review


Katharine E Halligan1, Antony Michealraj Kulandaimanuvel2, Andrea Cruz2, James T Felker3, Craig Daniels4, Michael D Taylor5, Sameer Agnihotri6,  
1 Department of Neurological Surgery, University of Pittsburgh School of Medicine; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh; Division of Pediatrics, Department of Hematology Oncology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA; Division of Pediatrics, Department of Hematology Oncology, Albany Medical Center, Albany, NY, USA
2 Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
3 Division of Pediatrics, Department of Hematology Oncology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
4 The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children; Department of Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
5 The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children; Department of Developmental and Stem Cell Biology Program, The Hospital for Sick Children; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada
6 Department of Neurological Surgery, University of Pittsburgh School of Medicine; John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh; Division of Pediatrics, Department of Hematology Oncology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA

Correspondence Address:
Dr. Sameer Agnihotri
John G. Rangos Sr. Research Center, UPMC Children's Hospital and University of Pittsburgh, 4401 Penn Avenue, PA 15224
USA

Abstract

Ependymomas are a lethal central nervous system (CNS) tumor found in both adults and children. Recent efforts have focused on risk stratification by classifying the molecular variants of CNS ependymoma. Despite this increased knowledge of molecular drivers, much less is known about the metabolism of these subgroups. Disruption of cellular metabolism can drive the transition of normal neuronal cells to tumor cells. A shift from anaerobic to aerobic metabolism as the primary energy source is a hallmark of cancer, promoting cancer cell proliferation, and avoidance of cellular apoptotic cues. This review aims to discuss the current knowledge regarding metabolism in ependymoma cells compared to normal brain cells and the implications of metabolic changes with regard to tumorigenesis, the tumor microenvironment, and possible targets for treatment.



How to cite this article:
Halligan KE, Kulandaimanuvel AM, Cruz A, Felker JT, Daniels C, Taylor MD, Agnihotri S. Pediatric posterior fossa ependymoma and metabolism: A narrative review.Glioma 2021;4:85-91


How to cite this URL:
Halligan KE, Kulandaimanuvel AM, Cruz A, Felker JT, Daniels C, Taylor MD, Agnihotri S. Pediatric posterior fossa ependymoma and metabolism: A narrative review. Glioma [serial online] 2021 [cited 2022 May 16 ];4:85-91
Available from: http://www.jglioma.com/text.asp?2021/4/4/85/335758


Full Text



 Introduction



Ependymomas are a lethal central nervous system (CNS) tumor found in both adults and children. Histologically classified as World Health Organization (WHO) I/II/III Grade tumors arising from glial cells, ependymoma is the third most common pediatric CNS tumor.[1],[2] While these tumors can be found in all three major anatomic compartments of the brain, they are most typically located intracranially (supratentorial region or posterior fossa) in children and as spinal lesions in adults. The current standard of care for ependymoma patients remains surgical resection followed by intense radiotherapy; this treatment confers a 7-year-event-free survival rate of approximately 65% in the pediatric population.[3],[4],[5] Unfortunately, due to catastrophic effects on the developing brain, there are limitations regarding the use of radiation treatment for ependymoma in infants and young children. In addition, cytotoxic chemotherapy has failed to show survival benefits.[5],[6],[7] However, a role for less intense maintenance chemotherapy is still being investigated.[8]

Recent efforts have focused on risk stratification by classifying the molecular variants of CNS ependymoma. More recently, ten subtypes based on location within the CNS, histopathologic and molecular characteristics reflecting genetic and epigenetic alterations have been classified by the 2021 WHO Classification of Tumors.[9],[10] The most prevalent subtype in pediatric patients is posterior fossa ependymoma located in the hindbrain of infants and children.[11] Posterior fossa ependymomas can be further subtyped into three distinct molecular entities, with clear clinical heterogeneity among the subtypes. Subependymoma is benign and classified as WHO Grade I tumors, while recently Myxopapillary Epenymoma is classified as Grade II. More aggressive and higher-grade posterior fossa ependymomas are classified as posterior fossa A ependymoma (PF-EPN-A) or posterior fossa B ependymoma (PF-EPN-B) [Figure 1].[12] Compared to PF-EPN-B ependymoma, PF-EPN-A ependymoma occurs more frequently in infants and younger children, has a poor prognosis, and exhibits alteration in polycomb repressor complex 2, a histone methyltransferase that is an important epigenetic regulator of histone H3.[13] There are currently nine PF-EPN-A subgroups and five PFB subgroups. Multiple research groups have shown that gain of chromosome 1q increases the risk of poor outcomes in PF-EPN-A ependymoma[7],[14],[15],[16],[17] but does not appear to alter prognosis in PF-EPN-B ependymoma.[18] More recently, an ultra-high-risk biologically distinct and extremely aggressive subgroup of PF-EPN-A ependymoma that is characterized by loss of chromosome 6q (independent of 1q status) has been identified.[18]{Figure 1}

Disruption of cellular metabolism can drive the transition of normal neuronal cells to tumor cells.[19] A shift from anaerobic to aerobic metabolism as the primary energy source is a hallmark of cancer, promoting cancer cell proliferation and avoidance of cellular apoptotic cues. This review aims to discuss the current knowledge regarding metabolism in ependymoma cells compared to normal brain cells and the implications of metabolic changes with regard to tumorigenesis, the tumor microenvironment, and PF-EPN-A treatment. Given the lack of advances in clinical PF-EPN-A treatment, understanding the role of metabolic dysregulation in these aggressive tumors is important and may yield new therapeutic strategies in future.

 Database Search Strategy



Literature review was electronically performed using PubMed database. The following combinations of key words were used to initially select the articles to be evaluated: Ependymoma and metabolism; ependymoma and glycolysis; ependymoma and tricarboxylic acid (TCA); ependymoma and oxidative phosphorylation; ependymoma and amino acid metabolism; ependymoma and epigenetics; brain tumors and epigenetics; pediatric brain tumors and epigenetics; ependymoma management; pediatric ependymoma management; brain tumors and metabolism; and pediatric brain tumors and metabolism. Most of the elected studies (80% of all references) were published from 2009 to 2020.

 Normal Brain Metabolism



Although the human brain only accounts for 2% of the body's total mass, it is responsible for 20% of the body's daily oxygen consumption and over half of the daily glucose intake.[20] Normal cells utilize glucose by generating pyruvate through glycolysis followed by oxidative metabolism to ultimately yield 36 adenosine triphosphates (ATPs), the main energy currency of the cell. In the majority of other human tissues, glucose is stored as glycogen, broken down to glucose, and released into the bloodstream to meet metabolic demands. Neural cells in the brain are unable to store glucose and thus rely on integrated cooperation with neighboring astrocytes that contain glycogen stores.[21] There is also evidence indicating that choroid plexus and ependymal cells are sites of glycogen synthesis and storage.[22] Astrocytes can take up glucose from the circulation via glucose transporter 1 (GLUT1) located on end feet that directly interact with capillary surfaces.[23] Glucose is ultimately converted to glycogen or metabolized to lactate, which is transported out of the astrocytes through monocarboxylate transporters (MCTs) and then taken up by neurons to be utilized. MCT1 is the predominant MCT isoform found in intracranial epithelial cells, astrocytes, and neuronal cells.[24] Lactate can then be oxidized to pyruvate through lactose dehydrogenase 1 and shuttled to the mitochondria for ATP generation.[25]

Astrocytes have high rates of glycolysis, utilizing glucose to generate ATP and lactate. They have high levels of glycolysis enzymes such as phosphofructokinase B3, an enzyme involved in the glucose input into the glycolytic pathway, and high levels of fructose 2,6-bisphosphate, an activator of the key glycolysis enzyme phosphofructokinase.[23] In contrast, neurons are thought to mainly exhibit oxidative metabolism of glucose, involving the mitochondrial TCA cycle and the electron transport chain. More recently, it has been suggested that neurons can utilize lactate efficiently and will preferentially use lactate over glucose in the presence of both.[26] Compared to astrocytes, neurons have low production of fructose 2,6-bisphosphate and PFK3B is essentially absent due to posttranscriptional downregulation (involving proteasomal degradation). High rates of glycolysis in neurons have been observed to increase oxidative stress and apoptosis, further indicating that neurons cannot maintain high glycolytic rates.[23] High glucose levels in neurons have also been shown to activate the hexose monophosphate pathway, resulting in nicotinamide adenine dinucleotide phosphate production. This indicates that neurons utilize glucose for maintaining antioxidant status rather than for bioenergetic purposes.[23],[27] Conversely, others have shown that neurons express all the enzymes needed to metabolize glucose through glycolysis,[28] and while PFK3B is posttranscriptionally downregulated in neurons, this is just one mechanism by which neurons can accomplish glycolysis for glucose metabolism.[29],[30] Yellen[31] reviewed several mechanisms by which neurons can increase their glycolytic capacity under stress, and they suggested the uncoupling of glycolysis and oxidative metabolism may be transient and not the preferred metabolic mechanism of neurons under stress.

Both glycogen storage and energy metabolism are compartmentalized throughout the brain. They appear to be highest in areas with the greatest synaptic density,[32] with the glycogen concentration being twice as high in grey matter compared to white matter.[33] Glycogen levels in these areas are strictly regulated by hormones (adrenaline and noradrenaline) and insulin signaling involving insulin-like growth factor.[20] There is also evidence for metabolic compartmentalization within both neurons and astrocytes, as evidenced by cellular heterogeneity in terms of the distribution of metabolites, proteins, ions, and organelles. Waagepetersen et al.[34] have described distinct mitochondria populations with different metabolic potential (based on α-ketoglutarate dehydrogenase activity) within astrocytes.

 Normal Glycolysis versus Posterior Fossa an Ependymoma Glycolysis



In addition to ATP generation to meet metabolic demands, cells also require biomolecules for the synthesis of lipids, nucleotides, and protein, as well as reducing agents for antioxidant protection.[35],[36],[37] Perhaps the most well-described difference between normal neuron metabolism and cancer cell metabolism is the shift from anaerobic to aerobic glycolysis known as the Warburg effect.[35] Tumor cells and other rapidly dividing cells can ferment glucose to lactate in the presence of oxygen. As reviewed by Agnihotri and Zadeh, the shift from oxidative metabolism to aerobic glycolysis in tumor cells is less efficient in energy generation due to the decreased potential yield of ATP through glycolysis but allows for the glycolysis and Kreb cycle intermediates to be shuttled into anabolic pathways to generate biomass.[27],[36],[37] Metabolic profiling suggests that glucose is abundantly enriched in PF-EPN-A ependymoma tissues compared to other pediatric brain tumors. Indeed, PF-EPN-A ependymoma cells growing in hypoxic conditions had superior glucose uptake than normoxia-treated cells, and blockade of GLUT1 decreased the proliferation of PF-EPN-A ependymoma cells. Upon glucose uptake, PF-EPN-A ependymoma cells use the glucose molecules for macromolecular synthesis by activating both the pentose phosphate pathway and serine/glycine metabolism by upregulating the expression of transketolase like 1, phosphoglycerate dehydrogenase, and phosphoglycerate dehydrogenase. Given that tumors such as ependymoma grow in hypoxic and nutrient-restricted conditions, the metabolic shift to aerobic glycolysis confers an advantage to the tumor cells as it allows adequate generation of both ATP and essential macromolecules for nucleotide, protein, and lipid synthesis required for cellular proliferation through diversion of carbon from glucose into biosynthetic pathways.[27] Ultimately, this allows PF-EPN-A cells to grow in harsh microenvironment cells that normal cells cannot grow nor survive in.

 Normal Tricarboxylic Acid Cycle versus Posterior Fossa an Ependymoma Tricarboxylic Acid Cycle



In the first comprehensive metabolic landscape study of PF-EPN-A ependymoma, several key findings regarding the TCA cycle (which is also known as the Krebs cycle or the citric acid cycle) in PF-EPN-A ependymoma emerged.[38] The TCA cycle is a critical metabolic pathway that regulates bioenergetics, biosynthetic pathways, and redox balance mechanisms. It is an amphibolic pathway involving anaplerosis and cataplerosis mechanisms that provide the nutrients to run the TCA cycle and remove the TCA cycle intermediates, respectively. In normal or neoplastic cells, glucose is converted into pyruvate, which is then imported into mitochondria to initiate the TCA cycle. In the TCA cycle, a series of enzymatic reactions generate reduced NADH and FADH2 (for use in the electron transport chain) and intermediates. The intermediates are used for fatty acid synthesis, gluconeogenesis, and amino acid biosynthesis. Additionally, they are used as essential cofactors for chromatin modifiers that regulate the physiological and disease epigenetic landscapes. Cancer cells exhibit robust metabolic plasticity, with both glycolysis and the TCA cycle/oxidative phosphorylation in mitochondria being functionally active and providing molecules for bioenergetic and biosynthetic processes. Certain mutations of TCA cycle-related genes can directly lead to enrichment of oncometabolites (2-hydroxyglutarate, succinate, and fumarate) and thereby inhibit the catalytic activity of histone demethylases and DNA demethylases. This leads to aberrant epigenetic patterns and may promote tumorigenesis by blocking differentiation. The tumor microenvironment (including hypoxia) and oncogene/tumor suppressor-dependent cell signaling events can selectively enrich certain intermediates of the TCA cycle to essentially regulate cellular and molecular processes involved in tumor formation and progression. Due to hypoxia and other factors, the TCA cycle in PF-EPN-A ependymoma is somewhat dysregulated but still functional. In actively proliferating PF-EPN-A ependymoma cells, due to dysregulation of the TCA cycle, the levels of TCA cycle intermediates such as succinate, fumarate, malate, and oxaloacetate are reduced, while citrate, isocitrate, and α-ketoglutarate levels are increased. As a result, the cellular ratio of α-ketoglutarate to succinate increases in PF-EPN-A ependymoma, promoting increased demethylation potential.[38] The histone 3 lysine 27 (H3K27) demethylases KDM6A/B use α-ketoglutarate as a cofactor to demethylate histones and promote transcriptional activation of genes that are important for PF-EPN-A ependymoma cell survival. In the TCA cycle, α-ketoglutarate is converted into citrate by reductive enzymatic reactions and exported into the cytosol via the citrate shuttle and then converted to acetyl-coenzyme A (CoA). Once in the cytosol, it serves as a precursor for lipid metabolism and as a cofactor for histone acetyltransferases (HATs). Thus, the TCA cycle plays a vital role in the dynamic regulation of the epigenetic landscape of lethal infantile ependymomas.

 Amino Acid Metabolism



Besides serving as precursors for protein synthesis, amino acids (and their metabolism) are very important for the sustained proliferation of cancer cells. This is because the related homeostasis mechanism controls gluconeogenesis, fatty acid synthesis, the urea cycle, redox balance, nucleotide synthesis, the TCA cycle, energy generation, and more importantly, epigenetic patterns in the cells.[39] Cancers can be auxotrophic regarding amino acids (depending on genetic makeup), and both gluconeogenic and ketogenic amino acids can be either synthesized (nonessential amino acids) or supplied throuh the tumor microenvironment and essential amino acids through oncogenic reprogramming mechanisms. Amino acid metabolism strongly contributes to the regulation of PF-EPN-A ependymoma nucleotide synthesis, redox homeostasis, protein regulation, and epigenetic regulation, selectively enriching specific metabolites/intermediates at the subcellular level. Glutamine and glutamate, which undergo catabolic processing to supply more α-ketoglutarate and acetyl-CoA, play pivotal roles in lipogenesis and histone acetylation in PF-EPN-A ependymoma. Metabolic plasticity in PF-EPN-A ependymoma cells can allow the glutamate pool to be increased using other amino acids such as proline, serine, glycine, and ornithine. On the other hand, amino acid homeostasis of methionine, glycine, and serine control the folate cycle, redox potential, and epigenetic regulation, including maintaining the basal level of histone 3 lysine 27 trimethylation (H3K27 me3), which is indispensable for PF-EPN-A ependymoma cell survival. PF-EPN-A ependymomas are lethal infantile malignancies that may originate during early embryonic development. Amino acid availability and metabolism in the developing embryonic brain can regulate physiological processes such as epigenetic and protein regulation involved in determining the fate of stem cells. However, this is poorly understood. Moving forward, to understand the metabolic and epigenetic plasticity of neoplasms, we need extensive investigations into the role of transcriptional and translational control of amino acid metabolism.

 How Metabolism Influences Epigenetics



The epigenetic landscape of any given cell, whether it is nonneoplastic, neoplastic, or differentiated, is dynamically linked to the availability of metabolites and the activity of metabolic pathways. Recent studies have highlighted that the localization and activity of metabolic enzymes can indeed regulate loci-specific gene expression and epigenomic profiles.[40],[41] Genomic aberrations, dysregulated cell signaling events, the tumor microenvironment, and dysfunctional/compromised immune landscapes can all enhance the activity of metabolic enzymes and thus control the availability of metabolites in tumor cells and tumor-associated cells.[42] The following cofactors are essential for catalytic activity: S-adenosylmethionine (SAM; methyl-donor cofactor) for histone methyltransferases and DNA methyltransferases;[43] Fe (II) and α-ketoglutarate for Tet methylcytosine dioxygenase and histone lysine demethylases (KDMs);[44] acetyl-CoA (acetyl-donating cofactor) for HATs;[45] and nicotinamide adenine dinucleotide (NAD+) for Class III histone deacetylases/sirtuins.

This interdependence involving metabolism and epigenetics is outlined in [Figure 2]. As mentioned above, various cancers essentially reprogram metabolic pathways and alter metabolite availability by potentiating oncogenic mechanisms. However, pediatric brain tumors that have a low mutational burden selectively hijack the cell types (cell of origin) that have potentiating oncogenic mechanisms or inhibiting tumor suppressor mechanisms to support rapid metabolic growth.[38] SAM is essential for histone methyltransferase activity, and the methionine cycle, which is a major source of SAM in the cell, is regulated by several critical metabolic pathways such as the folate cycle, trans-sulfuration pathway, and polyamine metabolism. H3K27 hypomethylation occurs in PF-EPN-A ependymoma through two distinct routes:[1] expression of EZH2 inhibitory protein (EZHIP/CXorf67) and elongin BC and polycomb repressive complex 2 associated protein (EPOP)[46] and[2] restricted availability of SAM. PF-EPN-A ependymoma has elevated expression of nicotinamide N-methyltransferase, which robustly consumes SAM as a cofactor and converts nicotinamide to 1-methyl nicotinamide.[47] By this process, nicotinamide N-methyltransferase outcompetes EZH2 methyltransferases for SAM and generates S-adenosylhomocysteine (SAH) in the cytosol, effectively blocking histone methyltransferases and DNA methyltransferases through direct competition for SAM. An unbalanced SAM/SAH ratio indicates aberrant cellular methylation potential.[48] Polyamine metabolite (putrescine, spermidine, and spermine) pathways, the other major SAM-consuming metabolic pathways, are upregulated in PF-EPN-A ependymoma. This further restricts the availability of SAM, leading to H3K27 hypomethylation and a less repressive chromatin signature.{Figure 2}

PF-EPN-A ependymoma exhibits hypomethylation and hyperacetylation at H3K27, indicating open chromatin and enhanced gene expression at specific loci.[38],[49] For hyperacetylation to occur at H3K27, PF-EPN-A ependymoma heavily depends on hypoxic conditions. Hypoxia increases the supply of the cofactor α-ketoglutarate to demethylases and thereby removes methyl groups at H3K27, and hypoxia also leads to acetyl-CoA production through reductive TCA cycle-mediated cataplerosis. Acetyl-CoA synthesized by ATP citrate lyase is imported into the nucleus and used as an acetyl-donating cofactor by HATs for hyperacetylation. When nutrient deprivation occurs in the tumor microenvironment, hypoxia promotes preferential uptake of acetate from outside the cell as a direct source of acetyl-CoA. Acetyl-CoA synthetase short-chain family members 2 and 3 (ACSS2/3) are involved in the metabolization of acetate into acetyl-CoA. When there is limited acetyl-CoA generated from the citrate pool, this mechanism serves to generate acetyl-CoA for lipid synthesis and histone acetylation.[50] In summary, while PF-EPN-A ependymoma does not have recurrent H3K27M, mutations to suppress histone hypermethylation, PF-EPN-A cells achieve hypomethylation by metabolic reprogramming to ensure that the essential cofactors and nutrients are supplied to inhibit the activity of histone methyltransferases. Demethylated histone is then hyperacetylated, using the enormous supply of acetyl-CoA through HAT activity in the nuclear compartment. H3K27 acetylation (H3K27Ac) in PF-EPN-A ependymoma leads to promoter activation, recruitment of enhancers and other transcriptional factors, and finally upregulation of gene expression for sustained cell survival, uncontrolled proliferation, and oncogenic cell signaling events. It will be of great interest how future studies incorporate metabolic therapies with the current standard of care treatments for PF-EPN-A such as radiation.

A major obstacle in the development of treatment for posterior fossa ependymoma is the paucity of known molecular features for targeting. Targeting tumor metabolism and the related regulation of epigenetics presents a very encouraging new treatment paradigm to pursue.

Limitations

This review is a summary of previously published articles related to metabolism and PF-EPN-A ependymoma. Some limitations include bias by authors, which could have led to incomplete or inadvertent interpretation of the existing literature. Other limitations of this review are accidental acts of omission by incomplete searches of the literature, which do not include all of the pertinent articles in this field, which regret to have included.

 Conclusion



Ependymomas are a lethal CNS tumor, and despite recent efforts focused on risk stratification by classifying the molecular variants, no new targeted treatments exist. Increased knowledge of the cellular metabolism in ependymoma cells compared to normal brain cells has enormous implications with regard to tumorigenesis, the tumor microenvironment, and possible targets for treatment. Targeting tumor metabolism and the related regulation of epigenetics presents a very encouraging new treatment paradigm to pursue.

Financial support and sponsorship

KEH was funded by an NIH T32 training grant from the Department of Paediatrics, University of Pittsburgh.

Conflicts of interest

There are no conflicts of interest.

References

1Gerstner ER, Pajtler KW. Ependymoma. Semin Neurol 2018;38:104-11.
2Vitanza NA, Partap S. Pediatric ependymoma. J Child Neurol 2016;31:1354-66.
3Merchant TE, Mulhern RK, Krasin MJ, Kun LE, Williams T, Li C, et al. Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J Clin Oncol 2004;22:3156-62.
4Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA. Conformal radiotherapy after surgery for paediatric ependymoma: A prospective study. Lancet Oncol 2009;10:258-66.
5Ramaswamy V, Hielscher T, Mack SC, Lassaletta A, Lin T, Pajtler KW, et al. Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: A retrospective multicohort analysis. J Clin Oncol 2016;34:2468-77.
6Souweidane MM, Bouffet E, Finlay J. The role of chemotherapy in newly diagnosed ependymoma of childhood. Pediatr Neurosurg 1998;28:273-8.
7Merchant TE, Bendel AE, Sabin ND, Burger PC, Shaw DW, Chang E, et al. Conformal radiation therapy for pediatric ependymoma, chemotherapy for incompletely resected ependymoma, and observation for completely resected, supratentorial ependymoma. J Clin Oncol 2019;37:974-83.
8DeWire M, Fouladi M, Turner DC, Wetmore C, Hawkins C, Jacobs C, et al. An open-label, two-stage, phase II study of bevacizumab and lapatinib in children with recurrent or refractory ependymoma: A Collaborative Ependymoma Research Network Study (CERN). J Neurooncol 2015;123:85-91.
9Pajtler KW, Mack SC, Ramaswamy V, Smith CA, Witt H, Smith A, et al. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 2017;133:5-12.
10Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol 2021;23:1231-51.
11Ramaswamy V, Taylor MD. Treatment implications of posterior fossa ependymoma subgroups. Chin J Cancer 2016;35:93.
12Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 2011;20:143-57.
13Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stütz AM, et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 2014;506:445-50.
14Kilday JP, Mitra B, Domerg C, Ward J, Andreiuolo F, Osteso-Ibanez T, et al. Copy number gain of 1q25 predicts poor progression-free survival for pediatric intracranial ependymomas and enables patient risk stratification: A prospective European clinical trial cohort analysis on behalf of the Children's Cancer Leukaemia Group (CCLG), Societe Francaise d'Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP). Clin Cancer Res 2012;18:2001-11.
15Andreiuolo F, Le Teuff G, Bayar MA, Kilday JP, Pietsch T, von Bueren AO, et al. Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification. PLoS One 2017;12:e0178351.
16Upadhyaya SA, Robinson GW, Onar-Thomas A, Orr BA, Billups CA, Bowers DC, et al. Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial. Neuro Oncol 2019;21:1319-30.
17Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M, et al. Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 2010;28:3182-90.
18Baroni LV, Sundaresan L, Heled A, Coltin H, Pajtler KW, Lin T, et al. Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q. Neuro Oncol 2021;23:1360-70.
19Marie SK, Shinjo SM. Metabolism and brain cancer. Clinics (Sao Paulo) 2011;66 Suppl 1:33-43.
20Bélanger M, Allaman I, Magistretti PJ. Brain energy metabolism: Focus on astrocyte-neuron metabolic cooperation. Cell Metab 2011;14:724-38.
21Magistretti PJ. Neuron-glia metabolic coupling and plasticity. J Exp Biol 2006;209:2304-11.
22Cataldo AM, Broadwell RD. Cytochemical identification of cerebral glycogen and glucose-6-phosphatase activity under normal and experimental conditions. II. Choroid plexus and ependymal epithelia, endothelia and pericytes. J Neurocytol 1986;15:511-24.
23Falkowska A, Gutowska I, Goschorska M, Nowacki P, Chlubek D, Baranowska-Bosiacka I. Energy metabolism of the brain, including the cooperation between astrocytes and neurons, especially in the context of glycogen metabolism. Int J Mol Sci 2015;16:25959-81.
24Pérez-Escuredo J, Van Hée VF, Sboarina M, Falces J, Payen VL, Pellerin L, et al. Monocarboxylate transporters in the brain and in cancer. Biochim Biophys Acta 2016;1863:2481-97.
25Rogatzki MJ, Ferguson BS, Goodwin ML, Gladden LB. Lactate is always the end product of glycolysis. Front Neurosci 2015;9:22.
26Hertz L, Peng L, Dienel GA. Energy metabolism in astrocytes: High rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 2007;27:219-49.
27Agnihotri S, Zadeh G. Metabolic reprogramming in glioblastoma: The influence of cancer metabolism on epigenetics and unanswered questions. Neuro Oncol 2016;18:160-72.
28Bak LK, Walls AB, Schousboe A, Ring A, Sonnewald U, Waagepetersen HS. Neuronal glucose but not lactate utilization is positively correlated with NMDA-induced neurotransmission and fluctuations in cytosolic Ca2+ levels. J Neurochem 2009;109 Suppl 1:87-93.
29Bolaños JP. Bioenergetics and redox adaptations of astrocytes to neuronal activity. J Neurochem 2016;139 Suppl 2:115-25.
30Herrero-Mendez A, Almeida A, Fernández E, Maestre C, Moncada S, Bolaños JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 2009;11:747-52.
31Yellen G. Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism. J Cell Biol 2018;217:2235-46.
32Kong J, Shepel PN, Holden CP, Mackiewicz M, Pack AI, Geiger JD. Brain glycogen decreases with increased periods of wakefulness: Implications for homeostatic drive to sleep. J Neurosci 2002;22:5581-7.
33Swanson RA, Sagar SM, Sharp FR. Regional brain glycogen stores and metabolism during complete global ischaemia. Neurol Res 1989;11:24-8.
34Waagepetersen HS, Hansen GH, Fenger K, Lindsay JG, Gibson G, Schousboe A. Cellular mitochondrial heterogeneity in cultured astrocytes as demonstrated by immunogold labeling of alpha-ketoglutarate dehydrogenase. Glia 2006;53:225-31.
35Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009;324:1029-33.
36Vander Heiden MG, Lunt SY, Dayton TL, Fiske BP, Israelsen WJ, Mattaini KR, et al. Metabolic pathway alterations that support cell proliferation. Cold Spring Harb Symp Quant Biol 2011;76:325-34.
37Lunt SY, Vander Heiden MG. Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 2011;27:441-64.
38Michealraj KA, Kumar SA, Kim LJ, Cavalli FM, Przelicki D, Wojcik JB, et al. Metabolic regulation of the epigenome drives lethal infantile ependymoma. Cell 2020;181:1329-45.e24.
39Palm W, Thompson CB. Nutrient acquisition strategies of mammalian cells. Nature 2017;546:234-42.
40Mews P, Donahue G, Drake AM, Luczak V, Abel T, Berger SL. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 2017;546:381-6.
41Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 2009;324:1076-80.
42Izzo LT, Affronti HC, Wellen KE. The bidirectional relationship between cancer epigenetics and metabolism. Annu Rev Cancer Biol 2021;5:235-57.
43Mentch SJ, Locasale JW. One-carbon metabolism and epigenetics: Understanding the specificity. Ann N Y Acad Sci 2016;1363:91-8.
44Anand R, Marmorstein R. Structure and mechanism of lysine-specific demethylase enzymes. J Biol Chem 2007;282:35425-9.
45Sivanand S, Viney I, Wellen KE. Spatiotemporal Control of Acetyl-CoA metabolism in chromatin regulation. Trends Biochem Sci 2018;43:61-74.
46Jain SU, Do TJ, Lund PJ, Rashoff AQ, Diehl KL, Cieslik M, et al. PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nat Commun 2019;10:2146.
47Ulanovskaya OA, Zuhl AM, Cravatt BF. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat Chem Biol 2013;9:300-6.
48Dai Z, Ramesh V, Locasale JW. The evolving metabolic landscape of chromatin biology and epigenetics. Nat Rev Genet 2020;21:737-53.
49Bayliss J, Mukherjee P, Lu C, Jain SU, Chung C, Martinez D, et al. Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas. Sci Transl Med 2016;8:366ra161.
50Li Y, Gruber JJ, Litzenburger UM, Zhou Y, Miao YR, LaGory EL, et al. Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia. Cell Death Dis 2020;11:102.