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| Status |
Public on Sep 12, 2023 |
| Title |
A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Pediatric high-grade gliomas (pHGG) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomic locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities—H3.3G34R/PDGFRAC235Yto FGFR inhibition, H3.3K27M/PDGFRAWTto PDGFRA inhibition, and H3.3K27M/PDGFRAWTand H3.3K27M/PPM1DΔC/PIK3CAE545Kto combined inhibition of MEK and PIK3CA. Moreover, H3.3K27Mtumors with PIK3CA, NF1, and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion, and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity.
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| Overall design |
7 mouse tumor models of K27M pHGG generated by in-utero electroporation of mutations, sequenced for single-nuclei. These 7 samples include 2 KPPMPIK replicates (H3.3K27M, PIK3CA E545K and PPM1D truncated), 3 KNF replicates (H3.3K27M, NF1 LOF and FGFR1-N457K) and 2 KPP replicates (H3.3K27M, P53 LOF and PDGFRA WT overexpression)
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| Contributor(s) |
McNicholas M, De Cola A, Hebert S, Faury D, Andrade AF, Jabado N, Kleinman CL, Pathania M |
| Citation(s) |
37011011 |
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| Submission date |
Sep 12, 2023 |
| Last update date |
Sep 13, 2023 |
| Contact name |
Claudia L Kleinman |
| E-mail(s) |
claudia.kleinman@mcgill.ca
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| Phone |
514-340-8222 25139
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| Organization name |
Lady Davis Institute for Medical Research
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| Department |
Human Genetics
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| Street address |
3999 Côte Ste-Catherine Road
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| City |
Montréal |
| State/province |
Québec |
| ZIP/Postal code |
H3T 1E2 |
| Country |
Canada |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA1015702 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE242998_RAW.tar |
761.8 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
| GSE242998_cell_metadata_KPPMPIK.tsv.gz |
355.0 Kb |
(ftp)(http) |
TSV |
| GSE242998_cell_metadata_KPP_KNF.tsv.gz |
2.2 Mb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
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