Transcription profiling of mouse medulloblastoma
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Junhao Mao
PROVIDER: E-GEOD-9299 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Dysregulatio of Hh signaling has been shown to be involved in the formation of human medulloblastoma. We generated a mouse model (CAGGS-CreER;R26-SmoM2) of Hh related tumors. We used microarray to profile gene expression in Hh induced mouse medulloblastoma and identified distinct classes of up-regulated or down-regulated genes during Hh dependent tumorigenesis . Keywords: Tumor vs wild type tissue
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Project description:We examined the transformation susceptibility of different cerebellar stem/progenitors by developing several new Group3 medulloblastoma murine models using orthotopic transplantation and in utero electroporation (EP)-based in vivo gene transfer with Cre/LoxP-mediated conditional Myc gene activation and loss of Trp53 function. We used microarrays to compared the transcriptome of these novel Group3 medulloblastoma mouse models to existing mouse models of medulloblastoma subgroups and used cross-species analysis to compare these models to human medulloblastoma subgroups This study aimed to investigate the cell of origin of Group3 MB using our orthotopical MYC model followed by a novel electroporation approach. Orthotopic cell-lineage specific MYC tumors were generated by enforced Myc expression in P6 GNPs isolated from P0-1 tamoxifen treated [Atoh1-CreER;Trp53fl/-] and [Prom1-CreER;Trp53fl/-] mice followed by cortical implants in immunocompromised mice. These tumors are referred to as Atoh1ER-MYC [dka072-075], Prom1-CreER [dka077-081]. The first Group3 MB models in which tumors developed in situ were generated by electroporation of plasmids containing Myc and dominant negative Trp53 flanked by loxP sites into the fourth ventricle of E13.5 Blbp-Cre [dka081, 087, 089, 090, 091 and blm121], Gad2-IRES-Cre [blm128-130 and blm134] and Ptf1a-Cre [blm135-137] mouse embryos. The gene expression profile of these tumors were compared to our previously published Group3 MB model as well as SHH and WNT models of medulloblastoma. For SHH subgroup medulloblastoma, [dka001-005, 009, 033 and 034] and [dka050-057], spontaneous medulloblastomas from [Cdkn2c-/-; Trp53Fl/Fl; Nestin-Cre] and [Cdkn2c-/-; Ptch1+/-] (Uziel et al.,2005 Genes Dev) were used, respectively. For Group3 medulloblastomas, [dka013-16, 049 and 065-067], in which Myc was overexpressed in Cdkn2c-/-, Trp53-/- cerebellar cells and implanted into the cortices of immunocompromised nude mice prior to tumor isolation. For WNT subgroup medulloblastomas [pgr003, 016 and 066], spontaneously developed tumors from CTNNB1+/lox (ex3); BLBP-Cre; Trp53Fl/Fl (Gibson et al., 2010, Nature) were removed for RNA extraction.
2015-02-13 | E-GEOD-65888 | biostudies-arrayexpress
Project description:In order to gain a better understanding of Ihh action during embryo implantation, we constitutively activated Smo in the murine uterus using the PRcre mouse model (PRcre/+SmoM2+; SmoM2). Female SmoM2 mice were infertile. They exhibited normal serum progesterone levels and normal ovulation, but ova failed to be fertilized in vivo and the uterus failed to undergo the artificially induced decidual response. SmoM2 mice exhibited uterine hypertrophy. The endometrium had a reduced number of uterine glands and the endometrial stroma lost its normal morphologic characteristics. Microarray analysis of 3 month old SmoM2 uteri demonstrated a chondrocytic signature and confirmed that constitutive activation of SmoM2 increased extracellular matrix production. Thus, constitutive activation of Smo in the mouse uterus alters the extracellular matrix which interferes with early pregnancy. Keywords: two group comparison We constitutively activated Hh signaling in the uterus by the expression of a mutant SmoM2 allele. We crossed these mice to the PRcre mouse model to constitutively activate Smo in the murine uterus (PRcre/+SmoM2+; SmoM2). High density DNA microarray analysis was performed on 3 month old control and SmoM2 uteri.
2010-04-13 | E-GEOD-17263 | biostudies-arrayexpress
Project description:This dataset includes the raw single-cell RNAseq data from Math1-Cre;SmoM2 mouse medulloblastoma model at P7.
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Project description:Misactivation of the Hedgehog (Hh) pathway can cause cancers such as medulloblastomas, the most common malignant brain tumor in children, and basal cell carcinomas, the most common cancer in the United States. Hedgehog signals are transmitted through primary cilia, where Hedgehog ligands bind to Patched1 and activate Smoothened through interactions with cilia-associated sterol lipids. The gene expression programs driving cellular responses to ciliary Hh signals are incompletely understood. Thus, to define Hh target genes, we performed RNA sequencing of cells after treatment with Hh ligands (Shh, Dhh, Ihh), cilia-associated lipids (7b,27-dihydroxycholesterol, 24(S),25-epoxycholesterol), or synthetic lipids or small molecules that activate Smoothened (20(S)-hydroxycholesterol, SAG). Treatment with Hh pathway agonists identified a core gene expression program comprised of 155 genes driving lipid synthesis, metabolism, signaling, adhesion, or angiogenesis. These datasets were integrated with RNA sequencing of Hh-human medulloblastomas (n=?), a Math1-Cre SmoM2 mouse genetic model of Hh-associated medulloblastoma (n=?), and human basal cell carcinomas (n=10) to ascertain how malignant Hh signaling differs from canonical Hh signaling. We discover a conserved response to ciliary Hh signals in human or mouse medulloblastomas, including known target genes such as Gli1 or Ptch1, and novel target genes such as Hsd11b1 or Retnla. Importantly, mechanistic studies reveal Hsd11b1 to be a putative negative regulator of Hh signaling that is dysregulated in malignancies. We further demonstrate Retnla to be a positive regulator of Hh signaling that drives expression of Hsd11b2, a druggable dependency underlying Hedgehog-associated medulloblastoma. Orthotopic implantation of neuroepithelial stem cells that overexpress either Hsd11b1 and Retnla demonstrate that tumors derived Hsd11ß1 overexpression are more primitive and less aggressive whereas Retnla overexpression forms tumors that are more differentiated and behave more aggressively. In sum, we illuminate the first comprehensive transcriptome of Hh signaling and highlight the intricate interplay between Hh signaling and lipid metabolism that Hh-dependent malignancies dysregulate to drive tumor progression.
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Project description:We performed ATAC-seq analysis, in order to understand the role of SmoM2 and truncated BRPF1 on the epigenetic landscape during medulloblastoma disruption
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Project description:We investigated how misactivation of the Hedgehog (Hh) pathway causes medulloblastoma, and found that Hh signaling induces its transcriptional effector GLI2 to bind the Cdk6 promoter, activate gene expression, and drive uncontrolled cell proliferation. Genetic or pharmacological inhibition of CDK6 repressed the growth of Hh-associated medulloblastoma and prolonged survival in vivo through inhibition of cell proliferation. These findings suggest that CDK6 antagonists may be effective therapies for Hh-associated cancers in humans.
2018-01-01 | GSE104633 | GEO
Project description:Aberrant sonic hedeghog signaling is implicated in the development of various cancer entities such as medulloblastoma. The canonical signaling cascade has been studied for years. Activation of GLI transcription factors was revealed as the driving force upon pathway activation. Phosphorylation by Proteinkinase A, Casein Kinase 1 and Glycogen Synthase Kinase 3 β has been found to influence the degradation of the GLI transcription factors. However, the deeper role of phosphorylation in the signal transduction remains unclear. We, therefore, applied comprehensive HPLC-MS/MS based phosphoproteomics to reveal phosphorylation dynamics underlying the chemical activation and inhibition of sonic hedgehog signaling in human medulloblastoma cells. Human medulloblastoma cells were treated with SAG (Hh pathway induction) and Vismodegib (Hh pathway inhibition) for 5 and 15 minutes. Our phosphoproteomic profiling revealed a central role of phosphorylation in the regulation of ciliary assembly, trafficking and signal transduction after 5 minutes treatment. ERK/MAPK signaling besides protein kinase A signaling and mTOR signaling were differentially regulated. Activation of Polo-like kinase 1 and inhibtion of Caseinkinase 2A1 was characteristic for Vismodegib treatment while SAG treatment induced Aurora kinase A activity. Distinctive phosphorylation of central players of sonic Hh signaling such as Smoothened, SUFU, Gli2 and Gli3 was obtained after 15 minutes treatment.
2021-09-08 | PXD013408 | Pride
Project description:Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrate a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidate the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in the tumor cells, showing the maximum inhibitory effect on Gli1 activity. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways , were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity. Gene expression data was generated (in replicates) from Medulloblastoma allografts collected at various time points and following low (40mpk) or high (80 mpk) or vehicle single dose (QD) or mutiple dose (BID) treatment with a SHH pathway inhibitor.
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