RNAseq of nestin-expressing murine brainstem progenitors infected with ACVR1 WT or R206H ACVR1 with and without H3.1K27M
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PROVIDER: PRJNA516939 | ENA |
REPOSITORIES: ENA
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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
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
Project description:Purpose: The purpose of this study was to assess the effect of targeting the Acvr1G328V mutation to oligoendrocyte lineage cells, on gene expression in the brainstem of mice at postnatal day 7 Methods: Total RNA was extracted from the brainstem of postnatal day 7 Acvr1+/+;Olig2Cre/+ and Acvr1floxG328V/+;Olig2Cre/+ littermates, processed using the Illumina TruSeq Stranded Total RNA Sample Preparation kit, and subjected to deep sequencing. Results: A total of 247 genes were differentially expressed between the genotypes, with a corrected p value of less than 0.05. Of these genes, 125 were upregulated while 122 were downregulated. Many of the most downregulated genes were mature oligodendrocyte markers, while several genes that control oligodendrocyte progenitor formation and function were upregulated. Conclusions: The Acvr1G328V mutation causes differentiation arrest of oligodendroglial lineage cells.
2020-02-14 | GSE142776 | GEO
Project description:The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Nestin+ and Nestin- GNPs (granule neuron precursors) were purified from Nestin-CFP/Math1-Cre/Ptch1-loxp cerebella at postnatal day 4 by FACs, and total RNA from these two cell populations were extracted, and then labeled and hybridized to Affymetrix Mouse Genome 430 2.0 arrays.
2016-08-09 | E-GEOD-84392 | biostudies-arrayexpress
Project description:The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies.
2016-08-09 | GSE84392 | GEO
Project description:To study the effect of the ACVR1 G328V mutation in tumor neurospheres with a background of NRASV12 overexpression and p53 knockdown. The goal of this study was to identify differentially expressed genes between mACVR1 NS v wt-ACVR1 NS.
2020-04-16 | GSE148732 | GEO
Project description:ACVR1-mutant posterior fossa ependymoma
| PRJNA802906 | ENA
Project description:Embryonic stem (ES) cells and ES cell-derived progeny characterized by nestin expression (including neural progenitors) were studied (three independent experiments). The mouse ES cell line R1 was cultured on a feeder layer of mouse embryonic fibroblasts (FL). ES cells were differentiated into nestin-positive cells for 4+8 days and 4+11 days according to the differentiation protocol by Rolletschek et al. (Mechanisms of Development 105, 93-104, 2001). The study was performed with three independent cell cultures (= triplicates). RNA was prepared from both undifferentiated ES cells and ES cell-derived nestin-positive cells, and from fibroblast feeder cells. Keywords = ES cell Keywords = nestin positive cells Keywords = feeder layer Keywords: other
2005-09-17 | GSE2375 | GEO
Project description: Not available
| S-EPMC3845444 | biostudies-literature
Project description:H1299 cells were stably transfected with the Oct4 promoter/GFP or Nestin promoter/GFP reporter vectors. By FACS, 106 cells expressing high levels of GFP were isolated and placed into cell culture for twenty-four hours. Total RNA was used. Bone morphogenetic proteins (BMP) are aberrantly expressed in most lung carcinomas. BMPs mediate cell fate decisions and self-renewal of stem cells. Inhibition of BMP signaling decreases the growth and induces cell death of lung cancer cells lines. It is not known whether the BMP signaling cascade is growth promoting in lung cancer cells expressing the stem cell markers Oct4 and/or nestin. Lung cancer cells expressing Oct4 or nestin were isolated from lung cancer cell lines by stably transfecting the Oct4 promoter or Nestin promoter expression vectors that activate the green fluorescent protein reporter. Our studies support that lung cancer cells activating the Oct4 or nestin promoter are different cell populations. Microarray and quantitative RT-PCR demonstrated that the expression levels of specific stem cell markers were different between the isolated Oct4 and nestin cells. Both the Oct4 and nestin populations were more tumorigenic that controls but histologically they were quite different. The isolated Oct4 and nestin cells also responded differently to inhibition of BMP signaling. Blockade of BMP signaling with the BMP receptor antagonist DMH2 caused significant growth inhibition in both the Oct4 and nestin cell populations but only increased cell death in the nestin population. DMH2 also induced the expression of nestin in the Oct4 population but not in the nestin cells. We also show that BMP signaling is an important regulator of the inhibitor differentiation proteins Id1 and Id3 in Oct4 and nestin cell populations
2014-07-30 | GSE49281 | GEO