CN133 hampers tumor growth in patient-derived pediatric ependymoma models
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PROVIDER: PRJNA578748 | ENA |
REPOSITORIES: ENA
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Project description:Pediatric ependymoma has relatively low frequencies of DNA mutations, which suggest that epigenetics may drive tumors. However, the epigenetic mechanisms for recurrent ependymoma are still poorly understood. Here, we performed longitudinal and comprehensive DNA methylation and gene expression analysis for recurrent pediatric ependymoma tumors from 10 patients, total 46 DNA methylomes (including primary tumors and matched recurrent tumors; normal pediatric brain tissues and PDOX tumors). Both RELA and PFA tumors maintained the subtype DNA methylation signatures during repeated relapses. We further identified the potential DNA methylation predictors, drivers and boosters and their potential regulated genes for recurrent ependymoma tumors. Increased DNA methylation levels within H3K4me1 enriched regions indicates disturbed functions of LSD1 gene in recurrent ependymoma tumors. Combining novel LSD1 inhibitor SYC-836 with radiation (XRT) significantly prolonged animal survival times in PDOX models of recurrent PFA ependymoma. Our PDOX models provide a unique platform for preclinical testing drugs and development of new therapy for pediatric recurrent ependymoma.
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Project description:HDACs are known to play crucial roles in cancer by deacetylating histones and non-histone substrates, leading to altered expression of genes involved in several cellular processes such as cell cycle control, apoptosis, DNA-damage response, angiogenesis, and autophagy, among othersto caracterize the transcriptomic changes induced by CN133 treatment on EPN cells, a microarray expression analysis of the EPP cell line treated with CN133 was performed
2019-10-22 | GSE139210 | GEO
Project description:We have generated and comprehensively characterized 30 patient-derived orthotopic xenograft (PDOX) models and 7 cell lines represeneting subgroups of medulloblastoma, high-grade glioma, atypical teratoid/rhabdoid tumor, ependymoma and pineoblastoma.
2018-10-25 | GSE99961 | GEO
Project description:We compared genomic characteristics of primary and first recurrent pediatric ependymoma to identify sub-group specific differences.
2016-09-11 | GSE50876 | GEO
Project description:We have generated and comprehensively characterized 30 patient-derived orthotopic xenograft (PDOX) models and 7 cell lines represeneting subgroups of medulloblastoma, high-grade glioma, atypical teratoid/rhabdoid tumor, ependymoma and pineoblastoma.
2018-10-25 | GSE99994 | GEO
Project description:Epigenetic Landscape of Pediatric Ependymoma Recurrence
| PRJNA658524 | ENA
Project description:Background: Epigenetic modifications have been shown to play an important role in the classification and pathogenesis of the pediatric brain tumor ependymoma, suggesting they are a potential therapeutic target. Methods: The effects of agents targeting epigenetic modifications on the growth and death of a panel of ependymoma cell lines was investigated, as well as toxicity to normal fetal neural stem cells. The ependymoma cell lines were characterized using DNA methylation profiling. Results: Agents targeting epigenetic modifications inhibited the growth and induced the death of ependymoma cells with variable efficiency. However, this was often not at clinically achievable doses. Additionally, DNA methylation profiling revealed a lack of similarity to primary ependymomas suggesting alterations were induced during culture. Toxicity to fetal neural stem cells was also seen at similar drug concentrations Conclusions: Agents targeting epigenetic modifications were able to inhibit the growth and induced the death of ependymoma cells grown in vitro. However, many agents were only active at high doses, outside clinical ranges, and also resulted in toxicity to normal brain cells. The lack of similarity in DNA methylation profiles between cultured cells and primary ependymomas questions the validity of using in vitro cultured cells for pre-clinical analysis of agents targeting epigenetic mechanisms and suggests further investigation using models that are more appropriate should be undertaken before agents are taken forward for clinical testing.
2018-12-26 | GSE112067 | GEO
Project description:We compared molecular characteristics of primary and recurrent pediatric ependymoma to identify sub-group specific differences. Gene expression profiles were used to identify unique immunobiologic sub-types of posterior fossa pediatric ependymoma. Gene expression profiles were generated from surgical tumor (ependymoma) (n=65) using Affymetrix HG-U133plus2 chips (Platform GPL570). Normalization was performed on our entire cohort of ependymoma. Of the 65 samples, a sub-set of 58 were used in the corresponding manuscript. Excluded samples are noted. Gene expression profiles were filtered to obtain gene expression of key immune cell markers. Comparative analyses between tumor samples were used to identifiy unique immunobiology between posterior fossa sub-groups.
2013-08-30 | E-GEOD-50385 | biostudies-arrayexpress
Project description:We compared molecular characteristics of primary and recurrent pediatric ependymoma to identify sub-group specific differences. Gene expression profiles were used to identify unique immunobiologic sub-types of posterior fossa pediatric ependymoma.
2013-08-30 | GSE50385 | GEO
Project description:ZFTA-RELA is the most recurrent genetic alteration seen in ependymoma, and sufficient to initiate tumors when expressed during mouse brain development. Despite ZFTA-RELA’s potent oncogenic potential, ZFTA-RELA gene fusions are observed exclusively in ependymoma and have never been documented in any other adult or pediatric malignancy. We hypothesized that specific chromatin modules accessible during brain development would render specific cells-of-origin at increased risk of transformation by ZFTA fusion proteins. To this end we performed integrated single cell ATAC and RNA-seq analysis (referred to as scMultimome) in mouse and human ependymoma tumors driven by the ZFTA-RELA fusion. We demonstrate that specific epi-developmental programs present in radial glia and regulated by Plagl1 are at direct risk of transformation. Oncoprotein engagement of this chromatin module leads to persistent oncogene expression, a failure to halt cellular proliferation, and initiate terminal cellular differentiation. Surprisingly, ependymomas exhibit significant heterogeneity across lineage differentiation programs, and continued activation of Plagl1 networks in differentiated cell types such as tumor neuronal-like cells contribute to tumor progression. These findings implicate specific chromatin modules in cells of origin as critical mediators of ependymoma initiation. Persistent activation and erosion of developmetn lineage programs serve as drivers of tumor development and contribute to the cellular heterogeneity of the tumor microenvironment.
2026-03-25 | GSE269937 | GEO