Whole genome analysis of pediatric patients with medulloblastoma
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ABSTRACT:
PROVIDER: EGAS00001006653 | EGA |
REPOSITORIES: EGA
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Project description:Medulloblastoma is the most common malignant pediatric brain tumor, and leptomeningeal dissemination (LMD) of medulloblastoma portends a poorer prognosis at diagnosis and is incurable at recurrence. The biological mechanisms underlying LMD in medulloblastoma are largely unclear. The Abelson (ABL) family of non-receptor tyrosine kinases has been implicated in cancer cell migration, invasion, adhesion, and chemotherapy resistance, and these kinases are upstream mediators of the oncogene c-MYC in fibroblasts. However, their role in medulloblastoma has not yet been explored. Therefore, the purpose of this work is to elucidate the role of the ABL kinases, ABL1 and ABL2, in medulloblastoma LMD. We show here that ABL1/2 mRNA is highly expressed in human medulloblastoma tumor samples and cell lines and that pharmacologic inhibition of ABL kinases results in medulloblastoma cell death. Knockdown of the ABL kinase genes ABL1 and ABL2 results in decreased adhesion to the extracellular matrix protein, vitronectin, and decreased medulloblastoma proliferation in a mouse model of medulloblastoma LMD (resulting in decreased tumor burden with subsequent increased overall survival. Further, both pharmacologic inhibition of ABL1/2 and ABL1/2 knockdown resulted in decreased c-myc expression, revealing a putative signaling pathway. In summary, this work highlights the potential role of ABL kinases in medulloblastoma LMD via c-myc expression.
2023-10-04 | GSE224691 | GEO
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 . Experiment Overall Design: Medulloblastoma samples and adjacent wild type cerebellar tissue from CAGGS-CreER;R26-SmoM2 mice were isolated for RNA extraction and hybridization on Affymetrix microarrays.
2008-06-16 | E-GEOD-9299 | biostudies-arrayexpress
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
2007-10-12 | GSE9299 | GEO
Project description:Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC’s role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knock-out mice in the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and delayed tumor onset. Premalignant lesions in cerebella of ASC-/-;ND2:SmoA1 mice displayed a striking decrease in number of ectopic progenitors. While proliferation rates decreased with ASC deletion, apoptosis and differentiation markers remained unchanged. Interestingly, ASC deficiency disrupted expression of genes in the TGF-ß pathway and increased the level of nuclear Smad3 in this medulloblastoma model. Together, these results demonstrate an unexpected requirement for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for anti-tumor therapy. reference x sample
2014-05-23 | E-GEOD-48682 | biostudies-arrayexpress
Project description:DDX3X is an ATP-dependent RNA helicase. Missense mutations in DDX3X gene are known to occur in WNT, SHH subgroup medulloblastomas. The role of DDX3X in medulloblastoma biology was studied by downregulating its expression in a SHH subgroup Daoy medulloblastoma cell line. DDX3X knockdown resulted in considerable reduction in proliferation, clonogenic potential and anchorage-independent growth of the medulloblastoma cells. Transcriptome analysis was performed to delineate the molecular mechanism underlying reduction in the malignant potential of the medulloblastoma cells upon DDX3X knockdown. Exogenous expression of three DDX3X missense mutants in the DDX3X knockdown cells could restore the malignant potential of the medulloblastoma cells.
2023-03-31 | GSE201967 | GEO
Project description:It has recently been demonstrated circular RNAs (circRNAs) involve in various biological processes, nevertheless, the function of circRNAs in medulloblastoma is still unknown. The present study aims to investigate the expression profiles of circRNAs in medulloblastoma and related mechanisms for tumorigenesis and progression of medulloblastoma.
2020-07-21 | GSE101739 | GEO
Project description:Origins of the brain tumor, medulloblastoma, from stem cells or restricted pro-genitor cells are unclear. To investigate this, we activated oncogenic Hedgehog signaling in multipotent and lineage-restricted CNS progenitors. We observed that normal unipo-tent cerebellar granule neuron precursors (CGNP) derive from hGFAP+ and Olig2+ rhombic lip progenitors. Hedgehog activation in a spectrum of early and late stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and that they retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hedgehog signaling promotes medulloblastoma from lineage-restricted granule cell progenitors. Gene expression profiling of cerebellar tumors generated from various early and late stage CNS progenitor cells. Experiment Overall Design: Group comparisons with biological replicates
2008-10-21 | E-GEOD-11859 | biostudies-arrayexpress
Project description:Purpose Integrated genomics approaches have identified at least four distinct biological variants in medulloblastoma: WNT, SHH, group C, and group D. Non-WNT/Non-SHH tumors are associated with metastatic dissemination and an unfavorable prognosis. Additional markers may enhance outcome prediction in Non-WNT/Non-SHH medulloblastomas. Experimental Design We combined transcriptomic and DNA copy-number analyses for 64 primary medulloblastomas. Bioinformatic tools were applied to discover marker genes of molecular variants. Differentially expressed transcripts were evaluated for prognostic value in the screening cohort. Immunopositivity for FSTL5 was correlated with molecular and prognostic subgroups for 235 non-overlapping medulloblastoma samples on two independent tissue microarrays (TMA). Results Unsupervised clustering analyses of transcriptome profiles confirmed four distinct molecular variants. Stable subgroup separation was achieved using only the 300 most varying transcripts. Specific distributions of clinical and molecular characteristics were noted for each cluster. Distinct expression patterns of FSTL5 in each molecular subgroup were confirmed by quantitative real-time PCR. Immunopositivity of FSTL5 identified a large cohort of patients (84 of 235 patients; 36%) at high risk for relapse and death. Importantly, over 50% of Non-WNT/Non-SHH tumors displayed FSTL5 negativity, delineating a large patient cohort with an excellent prognosis who would be considered intermediate/high-risk based on current molecular subtyping. Conclusions Comprehensive analyses of transcriptomic and genetic alterations delineate four distinct variants of medulloblastoma. The addition of FSTL5 immunohistochemistry to existing molecular stratification schemes can effectively identify those Non-WNT/Non-SHH tumors with a poor outcome. Immunohistochemical staining for FSTL5 could be a high-quality and practical tool for stratification and prognostication in future clinical trials of medulloblastoma. Whole-genome transcriptional profiling of human medulloblastomas. Subgrouping based on mRNA expression profiles. Fresh frozen tumor material was collected during tumor resection. Dye-swap design used for expression profiling. Reference was a pool of normal cerebellum tissue from 24 donors. Gene expression profiles illustrate distinct expression pattern at diagnosis. This submission represents the gene expression component of the study.
2011-07-01 | E-GEOD-28245 | biostudies-arrayexpress
Project description:The transcription factor OTX2 has been implicated as an oncogene in medulloblastoma, which is the most common malignant brain tumor in children. It is highly expressed in most medulloblastomas and amplified in a subset of them. The role of OTX2 in medulloblastoma and its downstream targets are unclear. Therefore, we generated D425 medulloblastoma cells in which we can silence endogenous OTX2 by inducible shRNA. Silencing of OTX2 strongly inhibited cell proliferation and resulted in a neuronal-like differentiation. Expression profiling of time courses after silencing showed a progressive change in gene expression for many cellular processes. Down regulated genes were highly enriched for cell cycle and visual perception genes, while up regulated genes were enriched for genes involved in development and differentiation. This shift in expression profiles is reminiscent to changes described to occur during normal cerebellum development. OTX2 is expressed in proliferating granular progenitor cells, but the expression diminishes when these cells exit the cell cycle and start differentiating. ChIP-on-chip analyses of OTX2 in D425 cells showed that cell cycle and perception genes were direct OTX2 targets, while regulation of most differentiation genes appears to be indirect. These analyses provide the first insight in the molecular network of OTX2, demonstrating that OTX2 is essential in medulloblastoma and directly drives proliferation by regulating the expression of cell cycle genes. Since many of these genes also correlate in expression with OTX2 in primary tumors, they might be potential targets for therapy in medulloblastoma patients. Keywords: OTX2, medulloblastoma, mRNA profiling *** This Series represents the gene expression component of the study. Three independent time course experiments of OTX2 silencing, and 1 control experiment in D425 medulloblastoma cells.
2012-07-03 | E-GEOD-22875 | biostudies-arrayexpress
Project description:The childhood brain tumour medulloblastoma includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant Beta-Catenin in WNT-medulloblastoma â an essentially curable form of the disease â induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoural chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma â a less curable disease subtype â contains an intact blood brain barrier, rendering this tumour impermeable and resistant to chemotherapy. Remarkably, the medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumour vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumours. We used microarrays to detail the global program of gene expression within endothelial cells from normal mouse hindbrain and genetic mouse models of different medulloblastoma subtypes to identify and verify up-regulated and down-regulated genes Endothelial cells were isolated from adult mouse hindbrain and genetic mouse models of Wnt and Shh-medulloblastoma using Cd-144 and Cd-105 antibodies based magnetic sorting. RNA was extracted and used for hybridization on Affymetrix microarrays. We sought to identify changes in endothelial gene expression patterns based on the surrounding microenvironment, so we purified endothelial cells from normal mouse brain or tumors from genetic mouse models. These include the Shh-medulloblastoma model (Ptch+/-; Ink4c -/-) and Wnt-medulloblastoma model (Blbp-Cre; mutant Ctnnb1+/-; p53-/-; mutant Pik3ca +/-)
2016-04-05 | E-GEOD-73753 | biostudies-arrayexpress