Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single-cell atlas of the developing brain to investigate the cellular origins of pediatric brain tumors

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE133531 | GEO | 2019/11/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Single-cell atlas of the developing brain to investigate the cellular origins of pediatric brain tumors

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.

| EGAS00001003368 | EGA

Expression data from E17.5 mouse brain regions

Project description:During brain development, layer 5 neurons distributed across most areas of the neocortex innervate the pontine nuclei (basilar pons) by the initiation and extension of collateral branches interstitially along their corticospinally extending axons. We used microarrays to compare gene expression profiles of brain areas that were projected (pontine nucleus, superior colliculus) and were not projected (cerebellum, olfactory bulb) by axon collaterals from the corticospinal tract in order to understand genetic programs that regulate axon collaterals formation.

2020-11-30 | GSE140761 | GEO

Evaluating cell culture reliability in pediatric brain tumor primary cells through DNA methylation profiling

Project description:In vitro models of pediatric brain tumors (pBT) are tools instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; and thus, ideally, they should recapitulate the original tumor. We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples, including 155 tumors and 86 pBT-derived cell cultures, and considering serum vs serum-free conditions, late vs early passages, and dimensionality (2D vs 3D cultures). We performed a t-SNE classification and identified differentially methylated regions in tumors compared to cell models. Early cell cultures recapitulate the original tumor, but serum media and 2D culturing were demonstrated to significant contribute to the divergence of DNAm profiles from the parental ones. All divergent cells clustered together acquiring a common deregulated epigenetic signature, suggesting a shared selective pressure. In conclusion, DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors.

2024-03-25 | GSE225810 | GEO

Gene expression data from ETMR cell line BT183

Project description:Gene expression data from this ETMR cell line was compared with gene expression data from primary ETMR tumors to search for potential drug targets in ETMR tumors.

2020-02-15 | GSE94985 | GEO

Integrated proteomics spotlight the proteasome as a pervasive therapeutic vulnerability in Embryonal Tumors with Multilayered Rosettes (ETMR)

Project description:Embryonal tumors with multilayered rosettes (ETMR) are rare malignant embryonal brain tumors. The prognosis of ETMR is poor and novel therapeutic approaches are desperately needed. Comprehension of ETMR tumor biology is based on only few previous molecular studies, which mainly relied on the analyses of nucleic acids. In this study, we explored integrated ETMR proteomics with the aim to identify novel therapeutic vulnerabilities in these deadly tumors. Using mass spectrometry, proteome data were acquired from FFPE tissue of 40 embryonal brain tumors (16 ETMR, 9 atypical teratoid/rhabdoid tumors (AT/RT), 15 medulloblastomas (MB)) and integrated with case-matched global DNA methylation data, publicly available transcriptome data, and proteome data of further pediatric brain tumors. Proteome-based cluster analyses grouped ETMR samples according to histomorphology, separating neuropil-rich tumors with neuronal signatures from primitive tumors with signatures relating to stemness and chromosome organization. Microdissection analyses highlighted the close relationship of ETMR histomorphology and proteome profiles, regardless of intra- or intertumoral comparisons. Integrated proteomics showcased that ETMR harbor proteasome regulatory proteins in abundancy, implicating their strong dependency on the proteasome machinery to safeguard proteostasis. Respectively, in vitro cell culture viability assays using embryonal brain tumor cell lines BT183 (ETMR), BT16 (AT/RT), and D283 (MB) highlighted that ETMR cells were highly vulnerable towards treatment with the CNS penetrant proteasome inhibitor Marizomib. In summary, histomorphology stipulates the proteome signatures of ETMR. Pervasive and histomorphology-independent abundancy of proteasome regulatory proteins in ETMR indicates a strong proteasome dependency throughout these tumors. As validated in cell culture experiments, proteasome inhibition poses a promising therapeutic option in ETMR.

2024-01-08 | PXD045268 | Pride

ETMR-like infantile cerebellar embryonal tumors in the extended morphologic spectrum of DICER1-related tumors

Project description:Description of two cases of ETMR-like cerebellar tumors with DICER1 mutations

2018-09-19 | GSE120122 | GEO

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [bulkRNAseq_ATRT_cellLines]

Project description:Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosisand the precise anatomic origin of brain tumors in the Rosa26; Cre-ERT2::Smarcb1flox/flox model. This cross-species analysis points to an extra-cerebral origin for MYC tumors. Additionally, we clearly distinguish SHH ATRT emerging from the cerebellar anterior lobe (CAL) from those emerging from the basal ganglia (BG) and intra-ventricular (IV) regions. Molecular characteristics point to the midbrain-hindbrain boundary as the origin of CAL SHH ATRT, and to the ganglionic eminence as the origin of BG/IV SHH ATRT. Single-cell RNA sequencing on SHH ATRT supports these hypotheses. Trajectory analyses suggest that SMARCB1 loss induces a de-differentiation process mediated by repressors of the neuronal program such as REST, ID and the NOTCH pathway.

2023-09-20 | GSE241733 | GEO

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [DNAmeth_EPICarray]

2023-09-20 | GSE242089 | GEO

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [bulkRNAseq_primaryATRT]

2023-09-20 | GSE241831 | GEO

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [scRNAseq_ATRT_CAL]

2023-09-20 | GSE241737 | GEO