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  • 1
    Online Resource
    Online Resource
    The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice
    Springer Science and Business Media LLC ; 2023
    In:  Oncogenesis Vol. 12, No. 1 ( 2023-07-05)
    Details
    In: Oncogenesis, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2023-07-05)
    Abstract: The tumor suppressor and chromatin modifier cAMP response element-binding protein binding protein (CREBBP) and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), a member of the MYC oncogene family, 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::Crebbp Fl/Fl ::lsl-MYCN mice were generated, which combine Crebbp deletion with overexpression of MYCN in neural stem cells (NSCs). Within eight months, these animals developed aggressive forebrain tumors. The first tumors were detectable in the olfactory bulbs of seven-day-old mice. This location raises the possibility that presumptive founder cells are derived from the ventricular-subventricular zone (V-SVZ). To examine the cellular biology of these tumors, single-cell RNA sequencing was performed, which revealed high intratumoral heterogeneity. Data comparison with reference CNS cell types indicated the highest similarity of tumor cells with transit-amplifying NSCs or activated NSCs of the V-SVZ. Consequently, we analyzed V-SVZ NSCs of our mouse model aiming to confirm 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. hGFAP-cre::Crebbp Fl/Fl ::lsl-MYCN mice thus provide a valuable tool to study tumor-driving mechanisms in a key neural stem/ progenitor cell niche.
    Type of Medium: Online Resource
    ISSN: 2157-9024
    URL: Article
    DOI: 10.1038/s41389-023-00481-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2674437-5
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  • 2
    Online Resource
    Online Resource
    BIOL-10. MOUSE MODELING OF PEDIATRIC MYCN GLIOMA REVEALS INTRATUMORAL HETEROGENEITY INCLUDING NEURONAL AND OLIGODENDROGLIAL LINEAGE SIGNATURES
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i7-i8
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i7-i8
    Abstract: Pediatric glioma of the subclass MYCN are highly aggressive tumors with a median age at diagnosis of 8 years and a median survival of only 14 months. Molecularly, they frequently carry MYCN amplifications, TP53 mutations or both of these alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and both biological as well as clinical details have not been fully addressed. In order to further investigate the biology and treatment options of these tumors, preclinical models are urgently needed. Therefore, we generated a genetically engineered model by breeding hGFAP-cre::Trp53Fl/Fl::lsl-MYCN mice, which carry a loss of Trp53 and show aberrant MYCN expression in neural precursors of the central nervous system. All such mice developed aggressive forebrain tumors early in lifetime that mimic their human counterparts regarding histology, DNA methylation, and gene expression. Single cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. To find new treatment options, we performed in vitro high-throughput drug screening on both, mouse and human tumor cells. Among 640 investigated anticancer compounds, Doxorubicin, Irinotecan, and Etoposide effectively suppressed the growth of tumor cells. As FDA-approved chemotherapeutics, these compounds are used for the treatment of other pediatric brain tumors. Repurposing them for the treatment of MYCN-driven high grade glioma could achieve a rapid transition to glioma treatment. We believe that our model will pave the way to improved treatment strategies for patients with these highly aggressive tumors.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.029
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2094060-9
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  • 3
    Online Resource
    Online Resource
    HGG-15. Generation of a novel mouse model for brain tumors of the DNA methylation class “GBM MYCN”
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i63-i63
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i63-i63
    Abstract: Multiple recent publications have described a highly aggressive subgroup of pediatric glioblastoma, which is clearly separable from other pediatric and adult glioblastoma based on its DNA methylation profile (GBM MYCN). These tumors almost exclusively occur in children and have a median overall survival of only 14 months. Many tumors in this group are driven by MYCN amplifications and harbor TP53 mutations. Otherwise, information about these tumors are still sparse and treatment is ineffective and causes severe side effects in many cases. In order to further investigate the biology and treatment options of these tumors, preclinical models are urgently needed. Here, we describe the generation of hGFAP-cre::TP53Fl/Fl::lsl-MYCN mice, which carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. These animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors by histology, global gene expression, and DNA methylation. In order to understand the developmental biology and intratumoral heterogeneity, we employed single cell RNA sequencing (scRNAseq) to the murine tumors with first results indicating a resemblance of tumor cells to committed oligodendrocyte precursors. We further show that both murine and human tumor cells are sensitive to AURKA inhibition in vitro, suggesting a potential new therapeutic option for improved patient care. We believe that further characterization and utilization of the model will pave the way to improved treatment strategies for patients with these highly aggressive tumors.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.230
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 4
    Online Resource
    Online Resource
    MODL-11. The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i170-i171
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i170-i171
    Abstract: CREBBP (cAMP response element-binding protein binding protein) and MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog), two essential proteins in central nervous system development that are described to be genetically altered in the same brain tumor entities, such as high grade glioma or medulloblastoma. Therefore, we hypothesized that alterations in both genes cooperate to induce brain tumor formation. In order to investigate molecular mechanisms and potential tumor formation, we established a novel mouse model combining a deletion of Crebbp with an overexpression of MYCN in neural stem cells (hGFAP-cre::CrebbpFl/Fl::lsl-MYCN). The animals developed highly aggressive forebrain tumors with 75 % penetrance already detectable in seven-day old mice, leading to tumor-related death within eight months. Although tumors mostly developed in the olfactory bulb region, we hypothesized that these tumors develop from subventricular stem cells that migrate into the olfactory bulb, where they settle and establish large solid tumors. In order to test this hypothesis, we analyzed neural stem cells (NSCs) derived from our mouse model. Compared to control cells, NSCs from transgenic mice have a significantly increased cell viability and proliferation in vitro and did not undergo full glial differentiation. In order to gain further insights into the cellular origin and biology of the tumors, we finally employed single cell RNA sequencing. Apart from a high intratumoral heterogeneity within the tumor cell population, data comparison with non-neoplastic CNS cell populations revealed a high similarity with transit-amplifying NSCs of the subventricular zone. Together, we were able to show the oncogenic potential of a combined loss of Crebbp and aberrant expression of MYCN in neural stem cells. This novel mouse model will be an important tool for understanding tumor-driving mechanisms and a valuable model for preclinical testing and will thereby help to improve patient care.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.634
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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