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

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: GSE228585 | 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 [array]

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.

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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.

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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.

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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.

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