Single-cell atlas of the developing brain to investigate the cellular origins of pediatric brain tumors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA551692 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9661650_1.fastq.gz | Fastqsanger.gz | |||
| SRR9661650_2.fastq.gz | Fastqsanger.gz | |||
| SRR9661651_1.fastq.gz | Fastqsanger.gz | |||
| SRR9661651_2.fastq.gz | Fastqsanger.gz | |||
| SRR9661652_1.fastq.gz | Fastqsanger.gz |
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Project description:Gene expression is finely regulated during development, and deregulation can lead to disease. In pediatric brain tumors (PBT), disruption of neurodevelopmental gene regulation programs are suspected to drive oncogenesis. However, the transcriptional landscape and genetic regulation processes of the healthy developing brain are not fully characterized, limiting our investigation of these tumors. We used single-cell RNA-sequencing to generate a transcriptomic atlas of >65,000 cells in the developing forebrain and pons in human and mouse, two regions where PBT commonly arise. We projected bulk RNA-seq profiles for a cohort of 198 PBT onto these cell types, followed by focused analysis of three PBT subtypes by single-cell profiling: WNT medulloblastoma, embryonal tumors with multilayered rosettes (ETMR), and atypical teratoid/rhabdoid tumors (ATRT). Altogether, we pinpoint stalled differentiation during developmental programs as a common etiological mechanism of PBT, providing a valuable resource to aid modeling and therapeutics.
2019-11-19 | GSE133531 | GEO
Project description:Gene expression is finely regulated during development, and deregulation can lead to disease. In pediatric brain tumors (PBT), disruption of neurodevelopmental gene regulation programs are suspected to drive oncogenesis. However, the transcriptional landscape and genetic regulation processes of the healthy developing brain are not fully characterized, limiting our investigation of these tumors. We used single-cell RNA-sequencing to generate a transcriptomic atlas of the developing forebrain and pons in human and mouse, two regions where PBT commonly arise. We projected bulk RNA-seq profiles for a cohort of 200 PBT onto these cell types, followed by focused analysis of three PBT subtypes by single-cell profiling: WNT medulloblastoma, embryonal tumors with multilayered rosettes (ETMR), and atypical teratoid/rhabdoid tumors (ATRT). In diffuse intrinsic pontine glioma (DIPG), we investigated the effect of removal of the driver H3K27M mutation on differentiation potential using primary tumor-derived cell lines. Altogether, for WNT medulloblastoma, ETMR, and DIPG, we pinpoint stalled differentiation during developmental programs as a common etiological mechanism of these tumors, providing a valuable resource to aid modeling and therapeutics.
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Project description:Epigenetics tightly regulates gene expression during brain development, which ensemble distinct cell types and form complicated functional brain organ. DNA methylation is an important mark which undergo dramatically changes during brain development. The disturb of this process will lead to various brain tumors. To study the concordant DNA methylation changes during normal brain development, we sequenced DNA methylome of pediatric brain tissues from autopsy with various ages. We systematically compared the DNA methylome of pediatric brain and adult brain and identified candidate DMRs that contribute to normal brain development. This comprehensive analysis will provide important epigenetic reference for human brain development which will be a valuable data to study the epigenetic mechanism of pediatric brain tumor.
2024-06-26 | GSE179086 | GEO
Project description:BackgroundDistinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the 3 most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas.MethodsWe used a single-nucleus atlas of the normal developing human cerebellum consisting of 176 645 cells as a reference for an in-depth comparison to 4416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques.ResultsWe find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study.ConclusionBased on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar "lineage of origin."
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Project description:The aim of the study was to compare the level of gene expression in pediatric brain tumors of various degrees of malignancy.
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Project description:Distinct DNA methylation landscape between pediatric brain and adult brain
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Project description:With the increasing use of immunotherapy in cancer, understanding the tumor immune microenvironment (TIME) has become increasingly important. There has been great success in treatment of some pediatric high-grade gliomas with immune checkpoint inhibition, however overall, the immune microenvironment in pediatric brain tumors remains poorly understood. Accordingly, we developed a clinical immune-oncology gene expression assay and used it to profile a diverse range of pediatric brain tumors with detailed clinical and molecular annotation, including a total of 1379 cases. Our findings demonstrate the critical importance of understanding the TIME to guide the prognosis and management of pediatric brain tumors. In pediatric low-grade gliomas we identified distinct patterns of immune activation with prognostic significance in BRAF V600E mutant tumors. In pediatric high-grade gliomas, we observed elevated inflammation and T cell infiltrates in tumors that have historically been considered immune cold, as well as genomic correlates of inflammation levels. In our cohort of mismatch repair deficient high-grade gliomas treated with immune checkpoint inhibition, we found that high tumor inflammation signature was a significant predictor of treatment response. Furthermore, we demonstrated the potential for multimodal biomarkers to improve the treatment stratification of these patients. Importantly, while overall patterns of immune activation were observed for histologically and genomically defined tumor types, there was nonetheless significant variability within each diagnostic entity, indicating that the immune response must be evaluated as an independent feature. In sum, in addition to the histology and molecular profile, this work establishes the importance of assessing and reporting on the tumor immune microenvironment as an essential axis of cancer diagnosis in the era of personalized medicine.
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