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.
Project description:We compared genomic characteristics of primary and first recurrent pediatric ependymoma to identify sub-group specific differences.
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.
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.
Project description:Ependymoma (EPN) is the third most common central nervous system (CNS) tumor in childhood and, recently, has been classified in nine robust molecular subgroups (Pajtler et al., 2015). However, molecular and clinical features of pediatric EPNs from Brazilian cohorts remain unexplored. Herein, we aimed to analyze the gene expression profile among three different molecular subgroups: ST-EPN-RELA, ST-EPN-YAP1 and PF-EPN-A.
Project description:we used whole-genome microRNA microarray expression profiling as a discovery platform to identify a subset of miRNAs that were differently expressed in CD44-positive pediatric posterior fossa ependymoma compared with CD44-negative ones.
Project description:Pediatric ependymoma is a devastating brain cancer marked by its relapsing pattern and lack of effective chemotherapies. This shortage of treatments is due to limited knowledge about ependymoma tumorigenic mechanisms. By means of single-nucleus chromatin accessibility and gene expression profiling of posterior fossa primary tumors and distal metastases, we reveal key transcription factors and enhancers associated with the differentiation of ependymoma tumor cells into tumor-derived cell lineages and their transition into a mesenchymal-like state. We identify NFkB, AP-1, and MYC as mediators of this transition, and show that the gene expression profiles of tumor cells and infiltrating microglia are consistent with abundant pro-inflammatory signaling between these populations. In line with these results, both TGF-b1 and TNF-a induce the expression of mesenchymal genes on a patient-derived cell model, and TGF-b1 leads to an invasive phenotype. Altogether, these data suggest that tumor gliosis induced by inflammatory cytokines and oxidative stress underlies the mesenchymal phenotype of posterior fossa ependymoma. This SuperSeries is composed of the SubSeries listed below.