The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-07-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-023-00481-3 |
| _version_ | 1797784444123217920 |
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| author | Melanie Schoof Gefion Dorothea Epplen Carolin Walter Annika Ballast Dörthe Holdhof Carolin Göbel Sina Neyazi Julian Varghese Thomas Karl Albert Kornelius Kerl Ulrich Schüller |
| author_facet | Melanie Schoof Gefion Dorothea Epplen Carolin Walter Annika Ballast Dörthe Holdhof Carolin Göbel Sina Neyazi Julian Varghese Thomas Karl Albert Kornelius Kerl Ulrich Schüller |
| author_sort | Melanie Schoof |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T00:39:57Z |
| format | Article |
| id | doaj.art-b15682d4e3694e03b88707ff4e3a4985 |
| institution | Directory Open Access Journal |
| issn | 2157-9024 |
| language | English |
| last_indexed | 2024-03-13T00:39:57Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj.art-b15682d4e3694e03b88707ff4e3a49852023-07-09T11:25:25ZengNature Publishing GroupOncogenesis2157-90242023-07-0112111110.1038/s41389-023-00481-3The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in miceMelanie Schoof0Gefion Dorothea Epplen1Carolin Walter2Annika Ballast3Dörthe Holdhof4Carolin Göbel5Sina Neyazi6Julian Varghese7Thomas Karl Albert8Kornelius Kerl9Ulrich Schüller10Research Institute Children`s Cancer CenterResearch Institute Children`s Cancer CenterInstitute of Medical Informatics, University of MünsterDepartment of Pediatric Hematology and Oncology, University Children’s Hospital MünsterResearch Institute Children`s Cancer CenterResearch Institute Children`s Cancer CenterResearch Institute Children`s Cancer CenterInstitute of Medical Informatics, University of MünsterDepartment of Pediatric Hematology and Oncology, University Children’s Hospital MünsterDepartment of Pediatric Hematology and Oncology, University Children’s Hospital MünsterResearch Institute Children`s Cancer CenterAbstract 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.https://doi.org/10.1038/s41389-023-00481-3 |
| spellingShingle | Melanie Schoof Gefion Dorothea Epplen Carolin Walter Annika Ballast Dörthe Holdhof Carolin Göbel Sina Neyazi Julian Varghese Thomas Karl Albert Kornelius Kerl Ulrich Schüller The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice Oncogenesis |
| title | The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice |
| title_full | The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice |
| title_fullStr | The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice |
| title_full_unstemmed | The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice |
| title_short | The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice |
| title_sort | tumor suppressor crebbp and the oncogene mycn cooperate to induce malignant brain tumors in mice |
| url | https://doi.org/10.1038/s41389-023-00481-3 |
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