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Series GSE73262 Query DataSets for GSE73262
Status Public on Feb 01, 2016
Title Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation, but resistant to temozolomide (FAIRE-seq)
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Introduction: Glioma stem cells isolated from human glioblastomas are resistant to radiation and cytotoxic chemotherapy and may drive tumor recurrence. Treatment efficacy may depend on the presence of glioma stem cells, expression of DNA repair enzymes such as methylguanine methyltransferase (MGMT), or transcriptome subtype. Methods: To model genetic alterations in the core signaling pathways of human glioblastoma, we induced conditional Rb knockout, Kras activation, and Pten deletion mutations in cortical murine astrocytes. Serial neurosphere culture, multi-lineage differentiation, and orthotopic transplantation were used to assess whether these mutations induced de-differentiation of cortical astrocytes into glioma stem cells. Efficacy of radiation and temozolomide was examined in vitro and in an allograft model in vivo. The effects of radiation on transcriptome subtype was examined by expression profiling. Results: G1/S-defective, Rb knockout astrocytes gained unlimited self-renewal and multi-lineage differentiation capacity, in both the presence and absence of Kras and Pten mutations. Only triple mutant astrocytes formed serially-transplantable glioblastoma allografts. Triple mutant astrocytes and allografts were sensitive to radiation, but expressed Mgmt and were resistant to temozolomide. Radiation induced a shift in transcriptome subtype of glioblastoma allografts from proneural to mesenchymal. Conclusion: A defined set of core signaling pathway mutations induces de-differentiation of cortical murine astrocytes into glioma stem cells. This non-germline genetically engineered mouse model mimics human proneural glioblastoma on histopathological, molecular, and treatment response levels. It may be useful in dissecting the genetic and cellular mechanisms of treatment resistance and developing more effective therapies.
Overall design Investigation of chromatin accessibility in astrocytes and glioblastoma cell lines
Contributor(s) Simon JM, Schmid RS, Miller CR
Citation(s) 26826202
Submission date Sep 21, 2015
Last update date May 15, 2019
Contact name Ryan Miller
Organization name University of North Carolina - Chapel Hill
Street address 6109B Neuroscience Research Building
City Chapel Hill
State/province North Carolina
ZIP/Postal code 27599
Country USA
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (9)
GSM1889812 AC1-FAIRE
GSM1889813 AC2-FAIRE
GSM1889814 T2-FAIRE
This SubSeries is part of SuperSeries:
GSE75592 Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation, but resistant to temozolomide
BioProject PRJNA296498
SRA SRP063945

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Supplementary file Size Download File type/resource
GSE73262_RAW.tar 9.0 Gb (http)(custom) TAR (of BW)
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Raw data are available in SRA
Processed data provided as supplementary file

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