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| Status |
Public on Jan 01, 2025 |
| Title |
Gliomagenesis mimics an injury response orchestrated by neural crest-like cells |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
To explore the early steps in glioma formation, we utilized conditional gene deletion and lineage tracing in tumour mouse models, coupled with serial magnetic resonance imaging to initiate and then closely track tumour formation. We isolated labeled and unlabeled cells at multiple stages -- before the first visible abnormality, at the time of the first visible lesion, and then through the stages of tumour growth -- and subjected each stage to single-cell profiling. We identify a malignant cell state with a neural crest-like gene expression signature that is highly abundant in the early stages, but relatively diminished in the late stage of tumour growth. Genomic analysis based on the presence of copy number alterations suggests that these neural crest-like states exist as part of a heterogenous clonal hierarchy that evolves with tumour growth. By exploring the injury response in the wounded normal mouse brain, we identify cells with a similar signature that emerge following injury and then disappear over time, suggesting that activation of an injury response programme occurs during tumourigenesis. Indeed, our experiments reveal a non-malignant injury-like microenvironment that is initiated in the brain following oncogene activation in cerebral precursor cells. Collectively, our findings provide insight into the early stages of gliomagenesis, identifying a unique stem cell-like state and an injury response programme tied to early tumour formation. This will have implications on glioblastoma therapies and raises exciting new possibilities for early disease diagnosis and prevention.
Some of the data in this series can also be explored through the following App link: stem-cells.ca.
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| Overall design |
1) Tumourigenesis atlas: we explored the early stages in tumour formation by combining glioma mouse modelling with serial magnetic resonance imaging (MRI) and single-cell profiling. We used genetically engineered mouse models to trace the fate of subpopulations of cells, with labelling initiated in either the pre- or postnatal brain. Brain tissue was harvested from mutant mice at four MRI-defined stages of tumourigenesis and samples were characterized by scRNA-seq.
2) Brain injury: to create an injury phenotype, we implanted an intracranial cannula in the right hemisphere of 4-6 week old non-mutant Sox2eGFP mice at stereotactic coordinates that place the cannula near the subventricular zone. The cannula was connected to an osmotic pump to slowly infuse the brain with saline over a period of 5 days. This resulted in structural tissue damage on the ipsilateral hemisphere.
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| Contributor(s) |
Hamed AA |
| Citation(s) |
39743595 |
| BioProject |
PRJNA1118442 |
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| Submission date |
Oct 01, 2024 |
| Last update date |
Jan 02, 2025 |
| Contact name |
Akram Hamed |
| E-mail(s) |
[email protected]
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| Organization name |
University of Toronto
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| Department |
Molecular Genetics
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| Street address |
NA
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| City |
Toronto |
| ZIP/Postal code |
NA |
| Country |
Canada |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (40)
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| Supplementary file |
Size |
Download |
File type/resource |
| GSE278511_brain.injury.samples.RData.gz |
1.4 Gb |
(ftp)(http) |
RDATA |
| GSE278511_malignant.cells.Sox2CEPPT.and.NestinCPPT.models.RData.gz |
535.7 Mb |
(ftp)(http) |
RDATA |
| GSE278511_tumourigenesis.atlas.RData.gz |
3.0 Gb |
(ftp)(http) |
RDATA |
SRA Run Selector |
| Raw data are available in SRA |
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