Hierarchical synergy of Pten, p53 and Rb pathways in high-grade astrocytoma induced in adult brain
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PROVIDER: PRJNA127619 | ENA |
REPOSITORIES: ENA
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Project description:Mutations in the PTEN, TP53 and RB1 pathways are obligate events in the pathogenesis of human glioblastomas, the highest grade of astrocytoma. To investigate synergy between these tumor suppressors in mice, we induced various combinations of compound deletions conditionally in astrocytes and neural precursors in the mature brain. The resulting highly penetrant astrocytomas showed a spectrum of histopathological variation reminiscent of human tumors, and ranged from grade III to grade IV (glioblastoma). Secondary somatic mutations varied depending on the combination of initiating deletions and were relevant to human disease. Receptor tyrosine kinase amplifications were frequent in tumors initiated by combined conditional deletion of Pten and Tp53, but not when Rb, Pten and Tp53 were simultaneously deleted. Multiple mutations within PI3K and Rb pathways were acquired, however, Mapk activation was not consistently detected in astrocytomas. Gene expression profiling revealed striking similarities to previously described human astrocytoma subclasses. A subset of astrocytomas initiated outside of proliferative niches in the adult brain.
2011-03-23 | GSE22927 | GEO
Project description:Mutations in the PTEN, TP53 and RB1 pathways are obligate events in the pathogenesis of human glioblastomas, the highest grade of astrocytoma. To investigate synergy between these tumor suppressors in mice, we induced various combinations of compound deletions conditionally in astrocytes and neural precursors in the mature brain. The resulting highly penetrant astrocytomas showed a spectrum of histopathological variation reminiscent of human tumors, and ranged from grade III to grade IV (glioblastoma). Secondary somatic mutations varied depending on the combination of initiating deletions and were relevant to human disease. Receptor tyrosine kinase amplifications were frequent in tumors initiated by combined conditional deletion of Pten and Tp53, but not when Rb, Pten and Tp53 were simultaneously deleted. Multiple mutations within PI3K and Rb pathways were acquired, however, Mapk activation was not consistently detected in astrocytomas. Gene expression profiling revealed striking similarities to previously described human astrocytoma subclasses. A subset of astrocytomas initiated outside of proliferative niches in the adult brain. Gene expression of 8 human brain samples including 2 normal brainstem and 6 brainstem low-grade gliomas were profiled using HG-U133 plus 2 arrays. Gene expression of 38 mouse tumor samples, including 24 Pten;p53 double knockout and 14 Pten;p53;Rb1 triple knockout, were profiled using Affymetrix Mouse Genome 430 v2 arrays. Copy number changes of 51 double knockout tumor samples were analysed using Roswell Park Cancer Institute 6.5k BAC arrays. Copy number changes of 21 triple knockout tumor samples were analysed using Agilent mouse genome CGH mocirarray 244A.
2011-03-23 | E-GEOD-22927 | biostudies-arrayexpress
Project description:Mutations in the PTEN, TP53 and RB1 pathways are obligate events in the pathogenesis of human glioblastomas, the highest grade of astrocytoma. To investigate synergy between these tumor suppressors in mice, we induced various combinations of compound deletions conditionally in astrocytes and neural precursors in the mature brain. The resulting highly penetrant astrocytomas showed a spectrum of histopathological variation reminiscent of human tumors, and ranged from grade III to grade IV (glioblastoma). Secondary somatic mutations varied depending on the combination of initiating deletions and were relevant to human disease. Receptor tyrosine kinase amplifications were frequent in tumors initiated by combined conditional deletion of Pten and Tp53, but not when Rb, Pten and Tp53 were simultaneously deleted. Multiple mutations within PI3K and Rb pathways were acquired, however, Mapk activation was not consistently detected in astrocytomas. Gene expression profiling revealed striking similarities to previously described human astrocytoma subclasses. A subset of astrocytomas initiated outside of proliferative niches in the adult brain. Gene expression of 8 human brain samples including 2 normal brainstem and 6 brainstem low-grade gliomas were profiled using HG-U133 plus 2 arrays. Gene expression of 38 mouse tumor samples, including 24 Pten;p53 double knockout and 14 Pten;p53;Rb1 triple knockout, were profiled using Affymetrix Mouse Genome 430 v2 arrays. Copy number changes of 51 double knockout tumor samples were analysed using Roswell Park Cancer Institute 6.5k BAC arrays. Copy number changes of 21 triple knockout tumor samples were analysed using Agilent mouse genome CGH mocirarray 244A.
| S-ECPF-GEOD-22927 | biostudies-other
Project description:Our findings suggested that cytokines were upregulated in p53 null primary prostate cells after deleting Rb and/or Pten. Rb and Pten deletion are important for prostate cancer progression.
2015-12-31 | GSE68904 | GEO
Project description:Our findings suggested that cytokines were upregulated in p53 null primary prostate cells after deleting Rb and/or Pten. Rb and Pten deletion are important for prostate cancer progression. p53-/- Rbf/f vs p53-/- Rbâf/âf primary prostate cells. Three independent experiments were performed. p53-/- Rbf/f vs p53-/- Rbâf/âf Ptenâf/âf primary prostate cells. Four independent experiments were performed.
2015-12-31 | E-GEOD-68904 | biostudies-arrayexpress
Project description:To determine the regulatory pathways necessary for astrocytoma formation within complex adult brain microenvironments, we engineered mice for adult astrocyte-specific disruption of key regulators (pRb, Kras and Pten). Drivers of all astrocytoma grades were identified using CreERTM-inducible alleles. Inactivation of pRb was necessary to initiate grade II disease, and was the only lesion to do so. Additional activation of Kras progressed disease to grade III, while further Pten inactivation facilitated grade IV (glioblastoma) progression. These outcomes were elicited whether somatic events were induced broadly or focally. In vivo inactivation of pRb, which induced astrocyte proliferation and apoptosis, activated the MAPK pathway, while Kras activation and Pten loss triggered PI3K pathways. TRPhet denotes mice with Inhibition of Rb, Over-expression of Kras and Deletion of one Copy of PTEN; TRPnull denotes mice with Inhibition of Rb, Over-expression of Kras and Deletion of both copies of PTEN; TR denotes mice with Inhibition of Rb, Over-expression of Kras.
2012-09-13 | GSE26002 | GEO
Project description:To understand molecular mechanisms underlying the synergy of Rb loss and E2F8 loss, we used gene expression profiling to assess molecular changes in Mx1-Cre-mediated knockout (KO) mice using RNA isolated from sorted Ter119+CD71high Erythroblasts. The top four upregulated and enriched pathways in the DKO mice included DNA replication, DNA damage response, DNA repair, and RNA processing. Interestingly, the majority of upregulated genes in the enriched sections of the four shared pathways contain E2f binding site(s) in their promoters, suggesting that Rb and E2F8 largely repress those genes through the E2f binding sites. Collectively, our data suggest that Rb and E2F8 co-regulate E2F-responsive genes. Spleen Ter119+CD71high cells were sorted from WT, E2f8 KO, Rb KO and E2f8;Rb DKO mice
2014-05-30 | E-GEOD-52157 | biostudies-arrayexpress
Project description:Development of gene sets after deleting Rb or Rb and Pten in p53 null background primary prostate cells
| PRJNA283993 | ENA
Project description:To determine the regulatory pathways necessary for astrocytoma formation within complex adult brain microenvironments, we engineered mice for adult astrocyte-specific disruption of key regulators (pRb, Kras and Pten). Drivers of all astrocytoma grades were identified using CreERTM-inducible alleles. Inactivation of pRb was necessary to initiate grade II disease, and was the only lesion to do so. Additional activation of Kras progressed disease to grade III, while further Pten inactivation facilitated grade IV (glioblastoma) progression. These outcomes were elicited whether somatic events were induced broadly or focally. In vivo inactivation of pRb, which induced astrocyte proliferation and apoptosis, activated the MAPK pathway, while Kras activation and Pten loss triggered PI3K pathways. TRPhet denotes mice with Inhibition of Rb, Over-expression of Kras and Deletion of one Copy of PTEN.
2012-09-13 | GSE26068 | GEO
Project description:To understand molecular mechanisms underlying the synergy of Rb loss and E2F8 loss, we used gene expression profiling to assess molecular changes in Mx1-Cre-mediated knockout (KO) mice using RNA isolated from sorted Ter119+CD71high Erythroblasts. The top four upregulated and enriched pathways in the DKO mice included DNA replication, DNA damage response, DNA repair, and RNA processing. Interestingly, the majority of upregulated genes in the enriched sections of the four shared pathways contain E2f binding site(s) in their promoters, suggesting that Rb and E2F8 largely repress those genes through the E2f binding sites. Collectively, our data suggest that Rb and E2F8 co-regulate E2F-responsive genes.
2014-05-30 | GSE52157 | GEO