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Series GSE235924 Query DataSets for GSE235924
Status Public on Sep 26, 2023
Title MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in mice
Organism Mus musculus
Experiment type Methylation profiling by array
Summary 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.
 
Overall design We cultured granule cell precursors isolated from Math1-creERT2::Smarca4fl/fl mice at P7 after tamoxifen-induced loss of SMARCA4 (injection at P3) and performed transduction with a lentiviral construct to drive overexpression of MYC.
These cells were transplanted into the cerebella of CD1nu/nu recipient mice, which successfully drove tumor formation.
Bisulphite converted DNA from three of these MYC/SMARCA4 tumors was hybridised to the Illumina Infinium Mouse Methylation BeadChip for a subsequent comparison to published global DNA methylation profiles of human tumors. Tumors 1,2,3 in this series correspond to tumors 1,3,4 in RNA sequencing analysis within the same project (GSE235625).
 
Contributor(s) Göbel C, Godbole S, Schoof M, Holdhof D, Kresbach C, Loose C, Schüller U
Citation(s) 37919824
Submission date Jun 27, 2023
Last update date Nov 16, 2023
Contact name Ulrich Schüller
E-mail(s) u.schueller@uke.de
Organization name University Medical Center Hamburg-Eppendorf
Lab Research Institute Children's Cancer Center
Street address Martinistraße 52
City Hamburg
ZIP/Postal code 20251
Country Germany
 
Platforms (1)
GPL30650 Infinium Mouse Methylation BeadChip
Samples (3)
GSM7512029 MYC/SMARCA4_tumor_1
GSM7512030 MYC/SMARCA4_tumor_2
GSM7512031 MYC/SMARCA4_tumor_3
Relations
BioProject PRJNA988041

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE235924_Matrix_processed.txt.gz 10.4 Kb (ftp)(http) TXT
GSE235924_RAW.tar 30.6 Mb (http)(custom) TAR (of IDAT)
Processed data included within Sample table
Processed data are available on Series record

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