Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells

ABSTRACT: Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using iPS cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the Sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Re-transplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model we identified LGALS1 to be a GLI target gene that is upregulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we demonstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression, and to identify novel putative targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106718 | GEO | 2020/07/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Recapitulation of genetic predisposition to medulloblastoma in human neuroepithelial stem cells

Project description:Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome, patients predisposed to medulloblastoma due to germline mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

| EGAS00001003620 | EGA

Implication of Nos2 inactivation on genomic changes in Ptch1+/- medulloblastomas (array-CGH)

2011-12-01 | E-GEOD-29199 | biostudies-arrayexpress

Implication of Nos2 inactivation on genomic changes in Ptch1+/- medulloblastomas (array-CGH)

2011-12-01 | GSE29199 | GEO

Implication of Nos2 inactivation on the transcriptome of developing cerebellum and Ptch1+/- medulloblastomas (mRNA)

2011-12-01 | GSE29192 | GEO

Implication of Nos2 inactivation on the transcriptome of developing cerebellum and Ptch1+/- medulloblastomas (mRNA)

Project description:The Ptch1+/- strain constitues an established mouse model for the Shh-driven type of medulloblastoma. Combined Ptch1+/- Nos2-/- mice show a two-fold increased incidence for this tumor. Here, the impact of Nos2 inactivation on medulloblastoma development was investigated by gene expression profiling of tumor samples as well as healthy cerebellum at different ages and genotypes. Medulloblastoma samples from three Ptch1+/- and six combined Ptch1+/- Nos2-/- mice were analyzed. Healthy cerebellum taken from mice at postnatal day nine, six weeks after birth, and about 1 year of age were analyzed for wildtype animals and the genotypes Ptch1+/-, Ptch1+/- Nos2-/-, and Nos2-/-. The cerebellar developmental stages at six weeks and one year were measured in three biological replicates, while samples taken at postnatal day six consisted of pooled individual specimen. These were measured in three replicates being amplified and labelled in separate reactions. All samples were subjected to two-color hybridizations against Universal Reference RNA (Stratagene) with color-switch experiments yielding two technical replicates, respectively.

2011-12-01 | E-GEOD-29192 | biostudies-arrayexpress

eff3fbb5-bba7-44ee-bb38-63d6722b3c86 - samples

Project description:Raw RNA-seq data for WT and 2 Gorlin NES cells, tumors derived from MYCN mis-expressed WT NES cells, tumors derived from Gorlin NES cells, and tumors derived from Gorlin NES cells transduced with mutant DDX3X (R351W and R534S) and CRISPR/Cas9 targeting GSE1 (each sample has 3 replicates/tumors except Gorlin NES cell tumors have 4). Raw whole exome sequencing data for WT and Gorlin 1 NES cells, tumors derived from MYCN mis-expressed WT NES cells, and tumors derived from Gorlin NES cells (each sample has 3 replicates/tumors except Gorlin NES cell tumors have 4). Raw data for amplicon sequencing of GSE1 and KDM3B at regions targeted by CRISPR/Cas9 in Gorlin NES cells.

| EGAD00001004990 | EGA

Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma (EdU-Seq)

Project description:Cancer is a multi-stage disease caused by sequential mutations; however, the molecular mechanism generating cancer-initiating mutations for many cancers is not well understood. Using the developing cerebellum as model system, here we delineate a molecular mechanism for tumor initiation in medulloblastoma (MB), the most frequent malignant pediatric brain tumor. Activation of the Sonic hedgehog (SHH) pathway is frequent in MB, with mutations in the tumor suppressor PTCH1 (a negative regulator of SHH signaling) being the most common initiating event for SHH-MB. However, how SHH as a developmental mitogen promotes early carcinogenesis in the cells of origin, granule cerebellar progenitors (GCPs), remains to be determined. Here we report that physiological exposure of GCPs to Shh causes a distinct form of DNA replication stress, altering DNA replication dynamics to increase both origin firing and fork velocity. Shh promotes DNA helicase loading and activation in GCPs, with increased levels of Cdc7-dependent replication origin firing. S-phase duration is reduced and hyper-recombination consequently occurs. Such elevated recombination causes copy-number neutral LOH, an event seen frequently at the PTCH1/ptch1 locus. Moreover, Cdc7 inhibition to attenuate origin firing in a MB mouse model is sufficient to reduce somatic recombination and preneoplastic tumor formation. We therefore establish that tissue-specific replication stress induced by Shh acts to promote LOH, which in tumor-prone Ptch1+/- GCPs can result in loss of this tumor suppressor, as an early cancer initiating event.

2020-07-20 | GSE147409 | GEO

Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma (RNA-Seq)

2020-07-20 | GSE147410 | GEO

Determining the chromatin accessibility profiles of functionally distinct SHH-medulloblastoma sub-populations

Project description:Using FACS sorting on SOX2-eGFP and MKi67-RFP mice on a Ptch1+/- background, we identified cycling& non-cycling stem cells and tumor bulk subpopulations in endpoint mouse SHH-subgroup medulloblastoma tumors, and determined their chromatin accessibility progiles to identify unique regulators of cell state.

2024-09-11 | GSE233993 | GEO

MYCN Drives Disparate Medulloblastoma from Human Embryonic and iPSC-Derived Stem Cells [array]

Project description:How tumors develop or respond to therapies vary significantly among species. Here we report that medulloblastoma (MB) the most frequent malignant childhood brain tumor can develop from human hindbrain neuro-epithelial stem (hbNES) cells or induced pluripotent stem cell (iPSC)-derived NES (NES) cells via MYCN overexpression in mice. NES tumors developed fast with leptomeningeal dissemination, while hbNES tumors formed significantly later with no dissemination. By using large cohorts of MB patients we show that tumors resemble a common subgroup of Sonic Hedgehog (SHH) MBs and that pluripotency and mTOR signaling correlate with poor prognosis. To conclude, both iPSC-derived and embryonic NES cells can be transformed into distinct humanized MB models valuable for identifying better diagnostic markers and drug targets.

2020-01-27 | GSE106727 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data