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Mouse modeling of pediatric glioma, MYCN reveals intratumoral heterogeneity including neuronal and oligodendroglial lineage signatures [array]

ABSTRACT: Pediatric glioma of the subclass MYCN are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. In order to understand the biology of these tumors better and to improve treatment options, we generated a genetically engineered model by breeding hGFAP-cre::TP53Fl/Fl::lsl-MYCN mice. All such mice developed aggressive forebrain tumors early in lifetime that mimic their human counterparts regarding histology, DNA methylation, and gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE227410 | GEO | 2023/09/25

REPOSITORIES: GEO

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Mouse modeling of pediatric glioma, MYCN reveals intratumoral heterogeneity including neuronal and oligodendroglial lineage signatures [RNA-Seq]

Project description:Pediatric glioma of the subclass MYCN are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. In order to understand the biology of these tumors better and to improve treatment options, we generated a genetically engineered model by breeding hGFAP-cre::TP53Fl/Fl::lsl-MYCN mice. All such mice developed aggressive forebrain tumors early in lifetime that mimic their human counterparts regarding histology, DNA methylation, and gene expression.

2023-09-25 | GSE227289 | GEO

Mouse modeling of pediatric glioma, MYCN reveals intratumoral heterogeneity including neuronal and oligodendroglial lineage signatures (scRNA, set 1)

2023-09-25 | GSE228585 | GEO

Mouse modeling of pediatric glioma, MYCN reveals intratumoral heterogeneity including neuronal and oligodendroglial lineage signatures (scRNA, set 2)

2023-09-25 | GSE237236 | GEO

The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice

Project description:The tumor suppressor CREBBP (CREB binding protein) and the MYCN proto-oncogene are critically involved in brain development. Both genes are frequently mutated in the same tumor entities, including high-grade glioma and medulloblastoma. Therefore, we hypothesized that alterations in both genes cooperate to induce brain tumor formation. For further investigation, hGFAP-cre::CrebbpFl/Fl::lsl-MYCN mice were generated, which combine a Crebbp deletion with an overexpression of MYCN in neural stem cells (NSCs). Within eight months, these animals developed aggressive forebrain tumors that resulted in tumor-related death with a penetrance of 75 percent. The earliest tumors were detectable in the olfactory bulbs of seven-day-old mice. In order to examine the cellular biology of these tumors, single-cell RNA sequencing (scRNA-seq) was performed, which revealed high intratumoral heterogeneity. Data comparison with reference CNS cell types indicated the highest similarity of tumor cells with transit-amplifying or activated NSCs of the ventricular-subventricular zone (V-SVZ). Consequently, we analyzed V-SVZ NSCs of our mouse model with the aim of confirming that the tumors originate from this stem cell niche. Mutant V-SVZ NSCs showed significantly increased cell viability and proliferation as well as reduced glial and neural differentiation in vitro compared to control cells. In summary, we demonstrate the oncogenic potential of a combined loss of function of CREBBP and overexpression of MYCN in this cell population. This mouse model thus provides a valuable tool to study tumor-driving mechanisms in a key neural stem/progenitor cell niche.

2023-07-13 | GSE214983 | GEO

Expression data from neuroblastoma of TH-MYCN/KI Alk mice

Project description:Neuroblastoma is an embryonal neoplasm that remains of dramatic prognosis in its aggressive forms. Activating mutations of the ALK tyrosine kinase receptor have been identified in sporadic and familial cases of this cancer. We generated knock-in mice carrying the two most frequent Alk mutations observed in neuroblastoma patients. We used microarrays to detail the global programme of gene expression underlying the impact of ALK mutations on neuroblastoma formation in a MYCN amplified background. We selected several murine neuroblastoma tumors for RNA extraction and hybridization on Affymetrix microarrays. We generated three groups of tumors: 10 MYCN amplified tumors, 11 MYCN amplified/ALK F1174L tumors and 10 MYCN amplified/ALK R1275Q tumors.

2014-06-24 | E-GEOD-46583 | biostudies-arrayexpress

Mouse modeling of pediatric glioma, MYCN reveals intratumoral heterogeneity including neuronal and oligodendroglial lineage signatures

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-09-25 | GSE227413 | GEO

Mouse modeling of pediatric glioma, MYCN reveals intratumoral heterogeneity including neuronal and oligodendroglial lineage signatures.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-09-25 | GSE237237 | GEO

Transcription profiling of human neuroblastoma cells with and without MYCN oncogene induction and doxorubicin treatment

Project description:Purpose: Clinical courses of neuroblastomas (NBs) range from rapid progression with fatal outcome despite intensive multimodality therapies to spontaneous regression. Amplified MYCN oncogene defines a subgroup with poor outcome. However, a substantial number of MYCN single-copy NBs exhibits an aggressive phenotype similar to that of MYCN-amplified NBs even in the absence of high MYCN mRNA and/or protein levels. Experimental Design: To identify shared molecular mechanisms that mediate the aggressive phenotype in MYCN amplified and single-copy high-risk NBs, we defined genetic programs evoked by ectopically expressed MYCN in vitro and analyzed them in high-risk versus low-risk NB tumors (n=49) using cDNA microarrays. Candidate gene and protein expression was validated in a separate cohort of 117 patients using quantitative PCR (QPCR) and in a panel of NB tumors using immunohistochemistry. Results: We identified a genetic signature characterized by Skp2, encoding the F-box protein of the SCFSkp2 E3-ligase, and a subset of MYCN and of E2F targets to be highly expressed in high-risk NBs. We validated the findings for Skp2 and analyzed its expression in relation to MYCN and E2F-1 expression in a separate cohort (n=117) using QPCR. Most importantly, high Skp2 expression proved to be a highly significant marker of dire prognosis independent of both MYCN status and disease stage, on the basis of multivariate analysis of event-free survival (hazard ratio, 3.54

2007-06-01 | E-CVDE-3 | biostudies-arrayexpress

Transcription profiling of neuroblastoma tumors with and without MYCN amplification

2007-06-01 | E-CVDE-2 | biostudies-arrayexpress

MicroRNA-Based Classification of Hepatocellular Carcinoma and Oncogenic Role of miR-517a

Project description:Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor due to activation of multiple cellular pathways and molecular alterations. Herein, we report the first molecular classification of 89 HCC based on the expression of 358 microRNAs and integrative genomic analysis. Three main subclasses of HCC were identified : two of them were associated with beta-catenin mutations or aggressive phenotype. A subset of the subclass of aggressive tumors (8/89, 9%) showed overexpression of a cluster of microRNAs located on chr19q13.41 (C19MC locus. We showed that miR 517a, representing C19MC, promoted cell proliferation, migration and invasion in vitro and induced the development of aggressive tumors in vivo suggesting its role as a novel oncogenic driver in HCC. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2011-02-17 | E-GEOD-20596 | biostudies-arrayexpress

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