MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in mice
Abstract Group 3 medulloblastoma is one of the most aggressive types of childhood brain tumors. Roughly 30% of cases carry genetic alterations in MYC, SMARCA4, or both genes combined. While overexpression of MYC has previously been shown to drive medulloblastoma formation in mice, the functional sig...
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01654-2 |
| _version_ | 1797636595501760512 |
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| author | Carolin Göbel Shweta Godbole Melanie Schoof Dörthe Holdhof Catena Kresbach Carolin Loose Julia Neumann Ulrich Schüller |
| author_facet | Carolin Göbel Shweta Godbole Melanie Schoof Dörthe Holdhof Catena Kresbach Carolin Loose Julia Neumann Ulrich Schüller |
| author_sort | Carolin Göbel |
| collection | DOAJ |
| description | Abstract Group 3 medulloblastoma is one of the most aggressive types of childhood brain tumors. Roughly 30% of cases carry genetic alterations in MYC, SMARCA4, or both genes combined. While overexpression of MYC has previously been shown to drive medulloblastoma formation in mice, the functional significance of SMARCA4 mutations and their suitability as a therapeutic target remain largely unclear. To address this issue, we combined overexpression of MYC with a loss of SMARCA4 in granule cell precursors. Both alterations did not increase proliferation of granule cell precursors in vitro. However, combined MYC overexpression and SMARCA4 loss successfully induced tumor formation in vivo after orthotopic transplantation in recipient mice. Resulting tumors displayed anaplastic histology and exclusively consisted of SMARCA4-negative cells although a mixture of recombined and non-recombined cells was injected. These observations provide first evidence for a tumor-promoting role of a SMARCA4 deficiency in the development of medulloblastoma. In comparing the transcriptome of tumors to the cells of origin and an established Sonic Hedgehog medulloblastoma model, we gathered first hints on deregulated gene expression that could be specifically involved in SMARCA4/MYC driven tumorigenesis. Finally, an integration of RNA sequencing and DNA methylation data of murine tumors with human samples revealed a high resemblance to human Group 3 medulloblastoma on the molecular level. Altogether, the development of SMARCA4-deficient medulloblastomas in mice paves the way to deciphering the role of frequently occurring SMARCA4 alterations in Group 3 medulloblastoma with the perspective to explore targeted therapeutic options. |
| first_indexed | 2024-03-11T12:37:20Z |
| format | Article |
| id | doaj.art-234db635bc2b43d68c70869f656e3164 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-11T12:37:20Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-234db635bc2b43d68c70869f656e31642023-11-05T12:31:58ZengBMCActa Neuropathologica Communications2051-59602023-11-0111111310.1186/s40478-023-01654-2MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in miceCarolin Göbel0Shweta Godbole1Melanie Schoof2Dörthe Holdhof3Catena Kresbach4Carolin Loose5Julia Neumann6Ulrich Schüller7Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfCenter for Molecular NeurobiologyDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfCenter for Molecular NeurobiologyDepartment of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfAbstract Group 3 medulloblastoma is one of the most aggressive types of childhood brain tumors. Roughly 30% of cases carry genetic alterations in MYC, SMARCA4, or both genes combined. While overexpression of MYC has previously been shown to drive medulloblastoma formation in mice, the functional significance of SMARCA4 mutations and their suitability as a therapeutic target remain largely unclear. To address this issue, we combined overexpression of MYC with a loss of SMARCA4 in granule cell precursors. Both alterations did not increase proliferation of granule cell precursors in vitro. However, combined MYC overexpression and SMARCA4 loss successfully induced tumor formation in vivo after orthotopic transplantation in recipient mice. Resulting tumors displayed anaplastic histology and exclusively consisted of SMARCA4-negative cells although a mixture of recombined and non-recombined cells was injected. These observations provide first evidence for a tumor-promoting role of a SMARCA4 deficiency in the development of medulloblastoma. In comparing the transcriptome of tumors to the cells of origin and an established Sonic Hedgehog medulloblastoma model, we gathered first hints on deregulated gene expression that could be specifically involved in SMARCA4/MYC driven tumorigenesis. Finally, an integration of RNA sequencing and DNA methylation data of murine tumors with human samples revealed a high resemblance to human Group 3 medulloblastoma on the molecular level. Altogether, the development of SMARCA4-deficient medulloblastomas in mice paves the way to deciphering the role of frequently occurring SMARCA4 alterations in Group 3 medulloblastoma with the perspective to explore targeted therapeutic options.https://doi.org/10.1186/s40478-023-01654-2Group 3 medulloblastomaMYCBRG1BAF complexChromatin remodeling |
| spellingShingle | Carolin Göbel Shweta Godbole Melanie Schoof Dörthe Holdhof Catena Kresbach Carolin Loose Julia Neumann Ulrich Schüller MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in mice Acta Neuropathologica Communications Group 3 medulloblastoma MYC BRG1 BAF complex Chromatin remodeling |
| title | MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in mice |
| title_full | MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in mice |
| title_fullStr | MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in mice |
| title_full_unstemmed | MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in mice |
| title_short | MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in mice |
| title_sort | myc overexpression and smarca4 loss cooperate to drive medulloblastoma formation in mice |
| topic | Group 3 medulloblastoma MYC BRG1 BAF complex Chromatin remodeling |
| url | https://doi.org/10.1186/s40478-023-01654-2 |
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