Targeting integrated metabolic and epigenetic pathways in lethal childhood ependymomas
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ABSTRACT:
PROVIDER: PRJNA555607 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9719240.fastq.gz | Fastqsanger.gz | |||
| SRR9719250.fastq.gz | Fastqsanger.gz | |||
| SRR9719241.fastq.gz | Fastqsanger.gz | |||
| SRR9719251.fastq.gz | Fastqsanger.gz | |||
| SRR9719242.fastq.gz | Fastqsanger.gz |
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Project description:Childhood Posterior Fossa-A ependymomas (PFAs) have limited treatment options. Integrated metabolic/epigenetic analyses performed to discover therapeutic targets in PFAs demonstrated enhanced glycolysis and TCA-cycle metabolism. PFAs exhibit low H3K27me3, as in H3K27M gliomas. Therefore, we subjected them to panobinostat which kills H3K27M cells, along with the metabolic inhibitor metformin. Combined treatment increased H3K27me3, suppressed metabolism and demonstrated potent therapeutic efficacy in vitro and in vivo, suggesting promising therapeutic strategies.
2022-07-01 | GSE134572 | GEO
Project description:Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.
| S-EPMC8762577 | biostudies-literature
Project description:Ependymomas are common childhood brain tumors that occur throughout the nervous system, but are most common in the pediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic SNVs. While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype (CIMP). Transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressor complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. CIMP-positive (CIMP+) hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically de-regulated but genetically bland. 10 primary posterior fossa ependymomas have been analyzed
2014-03-15 | E-GEOD-55920 | biostudies-arrayexpress
Project description:Ependymomas are common childhood brain tumors that occur throughout the nervous system, but are most common in the pediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic SNVs. While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype (CIMP). Transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressor complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. CIMP-positive (CIMP+) hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically de-regulated but genetically bland.
2014-03-15 | GSE55920 | GEO
Project description:Goal of the experiment : Recurrence is a frequent phenomenon in intracranial childhood ependymomas. To understand this process, we investigated whether the gene expression profiling of matched ependymomas at diagnosis and at relapse could reveal key molecular events involved in tumor progression. To gain new insight in this process and identify mechanisms associated with recurrence, we compared the CGH profiles of local recurrences with the corresponding initial tumors. Brief description We analyzed 17 tumor samples at diagnosis and a total of 27 paired recurrences. Recurrences analyzed occurred after surgery only in 12 cases, surgery plus chemotherapy only in 9 cases and any treatment plus radiotherapy in 6 cases. We compared the level of CGH profile for each tumor at diagnosis and recurrence relative to normal commercial DNA using Agilent 4x44K Human CGH microarrays.
2011-06-20 | E-TABM-1023 | biostudies-arrayexpress
Project description:1) Illumina 450K methylation profiles-48 posterior fossa ependymomas
2014-03-25 | GSE45353 | GEO
Project description:1) Illumina 450K methylation profiles-48 posterior fossa ependymomas NA
2014-03-25 | E-GEOD-45353 | biostudies-arrayexpress
Project description:A subset of genomically silent childhood posterior fossa ependymomas show reduced H3K27me3, global DNA hypomethylation, are more invasive, exhibit poor prognosis and epigenetically deregulated genes converge on radial glial factors, suggesting developing cerebellar radial glia as candidate cells-of-origin.
2016-11-28 | GSE87779 | GEO
Project description:Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
| EGAS00001000443 | EGA
Project description:Ependymomas are glial tumors that share morphologic similarities with ependymal cells. Here we laser microdissected ependymoma cells of 15 infratentorial tumors and generated gene expression profiles. These profiles were compared to those of 7 laser microdissected ependymal tissues. 10 000 laser microdissected cells of each of the 15 different infratentorial ependymomas and seven ependymal autopsy tissues were lysed and gene expression profiles were generated. Expression profiles of ependymomas were compared to those of ependymal cells.
2010-12-10 | E-GEOD-25604 | biostudies-arrayexpress