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Single-Cell RNA Sequencing of Pediatric Ependymoma uncovers Subclonal Heterogeneity associated with Patient Survival

ABSTRACT: Single-Cell RNA Sequencing of Pediatric Ependymoma uncovers Subclonal Heterogeneity associated with Patient Survival

PROVIDER: PRJNA785181 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17085100_1.fastq.gz	Fastqsanger.gz
	SRR17085100_2.fastq.gz	Fastqsanger.gz
	SRR17085101_1.fastq.gz	Fastqsanger.gz
	SRR17085101_2.fastq.gz	Fastqsanger.gz
	SRR17085102_1.fastq.gz	Fastqsanger.gz

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Single-Cell RNA Sequencing of Pediatric Ependymoma uncovers Subclonal Heterogeneity associated with Patient Survival

Project description:Ependymoma is a malignant glial tumor occurring throughout central nervous system, with one third of relapse rate. The increasing accessibility of single-cell transcriptome has accelerated our understanding of ependymoma. In this study, we generated a high-resolution single-cell dataset with a particular focus on the comparison of subclonal differences within tumor populations. As a proxy to traditional pseudotime analysis, we developed a novel trajectory scoring method to predict survival outcomes and specific molecular characteristics. Moreover, we identified putative cell-cell communication features between relapsed and primary samples and show upregulation of pathways associated with immune cell crosstalk. Our results reveal both inter- and intratumoral gene expression profiles and tumor differentiation and provide a framework for future studies on transcriptomic signatures of individual subclones in brain tumors at single-cell resolution, by which could complement existing published datasets and provide valuable insights into cell-type-specific properties and lay the foundation for therapeutic treatments of diseases.

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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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Expression data from human ependymoma

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.

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Expression data from human ependymoma

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Gene expression data from Brazilian pediatric ependymoma samples.

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