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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression data from RCAS PDGFB/Nestin tv-A glioma cells within Ptprd+/+p16-/- (n=2), Ptprd+/-p16-/- (n=2), and Ptrpd-/-p16-/- (n=3) mice.

ABSTRACT: PTPRD is a tumor suppressor of glioma that is frequently co-deleted with CDKN2A/p16. We show that Ptprd and p16 cooperate to promote gliomagenesis in the RCAS PDGFB / Nestin tv-A glioma mouse model. We found unique gene expression changes within tumor cells of Ptprd+/-p16-/- vs. Ptprd+/+p16-/- and Ptprd-/-p16-/- tumor cells. Neonatal mice were injected with RCAS PDGFB GFP. At symptoms, or at 12 weeks post injection, GFP+DAPI- tumor cells were sorted for RNA extraction and hybridization on Affymetrix microarrays. The mouse strain used was a mixed background of C57/BL6 and FVB/N. Ptprd mice were from Uetani et al. 2000 and p16/Nestin-tvA mice were from Tchouganouva et al. 2007.

ORGANISM(S): Mus musculus

SUBMITTER: Timothy Chan

PROVIDER: E-GEOD-55061 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis.

Ortiz Berenice B Fabius Armida W M AW Wu Wei H WH Pedraza Alicia A Brennan Cameron W CW Schultz Nikolaus N Pitter Kenneth L KL Bromberg Jacqueline F JF Huse Jason T JT Holland Eric C EC Chan Timothy A TA

Proceedings of the National Academy of Sciences of the United States of America 20140519 22

PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse mod ...[more]

PMID: 24843164

Similar Datasets

Expression data from RCAS PDGFB/Nestin tv-A glioma cells within Ptprd+/+p16-/- (n=2), Ptprd+/-p16-/- (n=2), and Ptrpd-/-p16-/- (n=3) mice.

Project description:PTPRD is a tumor suppressor of glioma that is frequently co-deleted with CDKN2A/p16. We show that Ptprd and p16 cooperate to promote gliomagenesis in the RCAS PDGFB / Nestin tv-A glioma mouse model. We found unique gene expression changes within tumor cells of Ptprd+/-p16-/- vs. Ptprd+/+p16-/- and Ptprd-/-p16-/- tumor cells.

2014-06-02 | GSE55061 | GEO

Novel cancer gene discovery using a forward genetic screen in RCAS-PDGFB driven gliomas

Project description:Here we describe the use of a high-throughput pipeline coupled to the commonly used tissue-specific retroviral RCAS-TVA mouse tumor model system. Utilizing next generation sequencing, we show that retroviral integration sites can be reproducibly detected in malignant stem cell lines generated from RCAS-PDGFB-driven glioma biopsies.

2022-07-05 | GSE207264 | GEO

Mus musculus

Project description:Expression data from RCAS PDGFB/Nestin tv-A glioma cells within Ptprd+/+p16-/- (n=2), Ptprd+/-p16-/- (n=2), and Ptrpd-/-p16-/- (n=3) mice.

| PRJNA238357 | ENA

Gene expression profiling of mouse tumors arising from Keratin 6-positive mammary cells

Project description:Conventional transgenic and knockout models do not allow selective introduction of oncogenic alterations into the progenitor population of mammary cells; thus, the role of progenitor cells in mammary tumorigenesis is yet unknown. By generating transgenic mice expressing tva – encoding the receptor for avian leukosis virus subgroup A (ALV/A) – from the Keratin 6a (K6) gene promoter, we found that K6+ mammary cells are bipotential progenitor cells, but not stem cells. These K6+ cells were readily induced to form tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding polyoma middle T antigen. Compared with tumors induced by the same oncogene-expressing virus in transgenic mice expressing tva from the commonly used MMTV LTR or other murine models of breast cancer, tumors in this K6-tva line were unique in that they resemble the normal breast-like subtype of human breast cancer. Consequently, these observations suggest that the cell of origin affects mammary tumor phenotypes. This K6-tva model may be useful for preclinical testing of targeted therapy for normal-like breast cancers in patients. Keywords: Three group comparison We carried out Affymetrix array analysis of five RCAS-PyMT-induced tumors each from K6-tva mice and MMTV-tva mice, as well as five mammary tumors from MMTV-PyMT transgenic mice.

2011-05-09 | E-GEOD-20614 | biostudies-arrayexpress

Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

Project description:Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAs/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76 gene signature DNA repair panel. Consistently, compared to Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor. 5 different experimental conditions were compared (including GFP, PDGFB, PDGFB in conjunciton with Akt1, Akt2, or Akt3) with 3 mice per treatment

2015-02-24 | E-GEOD-66177 | biostudies-arrayexpress

RNAseq of nestin-expressing murine brainstem progenitors infected with ACVR1 WT or R206H ACVR1 with and without H3.1K27M

Project description:Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, resulting in the death of 200-300 children each year in the United States. Recently it was discovered that approximately 25% of all DIPG cases harbor activating mutations in ACVR1, a gene that encodes Activin A receptor (ALK2), a receptor in the bone morphogenetic protein (BMP) pathway, and that DIPGs with ALK2 mutations commonly harbor an H3.1K27M mutation. Herein, we used the RCAS/TVA retroviral system to study the effects of ACVR1 mutations and H3.1K27M on DIPG pathogenesis. In vitro expression of R206H ACVR1 with and without H3.1K27M in nestin-expressing brainstem progenitors resulted in upregulation of mesenchymal markers and gene set enrichment analysis (GSEA) revealed Stat3 pathway activation. Neonatal expression of ACVR1 R206H or G328V in combination with H3.1K27M and p53 deletion in nestin-expressing brainstem progenitors induced glioma-like lesions expressing mesenchymal markers with Stat3 activation but was not sufficient for full gliomagenesis. In combination with platelet-derived growth factor A (PDGFA) signaling, ACVR1 R206H and H3.1K27M significantly decreased survival and increased tumor incidence. We demonstrate that targeting the BMP signaling pathway may be an effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs. Exogenous Noggin expression at tumor initiation significantly increased tumor latency and treatment of ACVR1 R206H mutant murine DIPGs with LDN212854, an ACVR1 inhibitor, significantly prolonged their survival. We confirm relevance of our model to the human disease as human DIPG models with ACVR1 mutations were also sensitive to treatment with LDN212854 in vitro. Altogether, our studies demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile in part due to Stat3 activation, and identify LDN212854 as a promising compound to treat children with DIPG.

2019-01-25 | GSE125627 | GEO

A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M I

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is increased when tumorigenesis is initiated in Nestin+ cells. Therefore, we need to find how the tumorigenic effects of H3.3K27M are more oncogenic in Nestin+ cells than Olig2+ cells.

2021-10-05 | GSE184934 | GEO

RNAseq analysis of murine brainstem gliomas with and without H3.3K27M

Project description:Using the RCAS/tv-a system, we induced murine brainstem gliomas (PDGF-B; p53 loss using RCAS-Cre with and without H3.3K27M) in Nestin tv-a; p53 floxed mice

2017-05-11 | GSE98765 | GEO

Effects of the Combination Therapy of a CDK4/6 and a MEK inhibitor in a Mouse Model of Diffuse Midline Glioma

Project description:Diffuse intrinsic pontine glioma (DIPG) arises in the brainstem of children, leading tumor-related death among children. A heterozygous histone H3.3K27M mutation has been shown to occur in ~80% of DIPGs, and results in brainstem gliomagenesis. There is no clinical trial for the patients with DIPG that proved to prolong survival time so far. Recently, CDK4/6 inhibitor showed feasibility and early therapeutic effect against DIPG. Also, recent research with human DIPG specimens have detected the MAPK pathway highly activated. Here, we evaluated a novel combination therapy with CDK4/6 inhibitor and MEK inhibitor to the mouse DIPG model. In order to generate DIPG‐bearing mice, we are using the RCAS/Tv‐a system, with which we are able to target specific genetic alterations in RCAS viruses (avian retroviruses) to specific cells‐of‐origin using transgenic Tv‐a‐expressing mice (Tv‐a being the receptor for RCAS viruses). We injected P3‐P5 Nestin-Tv-a;p53fl/fl mice (C56Bl/6 background) with RCAS‐PDGF‐A + RCAS‐H3.3K27M, and RCAS-Cre. The mice are treated with vehicle (methylcellurose), ribociclib as monotherapy, trametinib as monotherapy, and ribociclib and combination as combination. For short-term use, tumor tissues treated with ribociclib showed cytostatic effect, and those treated with trametinib showed cytotoxic effect, and those with combination showed both. Long-term use showed that combination therapy modestly prolonged mice survival compared with vehicle. Therefore, we need to find how DIPG showed registence to the long-term chemotherapy.

2021-09-28 | GSE184786 | GEO

A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M II

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A overexpression, along with p53 deletion, resulted in gliomas. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. Interestingly, H3K27 trimethylation was decreased with H3.3K27M induction even in Olig2+ cells. Therefore, we need to find if there is transcriptional changes for the tumorigenesis with H3.3K27M in Olig2+ cells.

2021-10-05 | GSE184935 | GEO

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