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  • 1
    Language: English
    In: Acta neuropathologica, April 2012, Vol.123(4), pp.463-4
    Description: Byline: Stefan Pfister (1) Author Affiliation: (1) German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Heidelberg, Germany Article History: Registration Date: 27/02/2012 Online Date: 07/03/2012
    Keywords: Cerebellar Neoplasms -- Pathology ; Medulloblastoma -- Pathology
    ISSN: 00016322
    E-ISSN: 1432-0533
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  • 2
    In: Nature, 2013, Vol.497(7451), p.624
    Description: Recent exon-sequencing studies of human tumours have revealed that subunits of BAF (mammalian SWI/SNF) complexes are mutated in more than 20% of all human malignancies, but the mechanisms involved in tumour suppression are unclear. BAF chromatin-remodelling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure and the placement of Polycomb repressive complex 2 (PRC2) across the genome. Several proteins dedicated to this multisubunit complex, including BRG1 (also known as SMARCA4) and BAF250a (also known as ARID1A), are mutated at frequencies similar to those of recognized tumour suppressors. In particular, the core ATPase BRG1 is mutated in 5-10% of childhood medulloblastomas and more than 15% of Burkitt's lymphomas. Here we show a previously unknown function of BAF complexes in decatenating newly replicated sister chromatids, a requirement for proper chromosome segregation during mitosis. We find that deletion of Brg1 in mouse cells, as well as the expression of BRG1 point mutants identified in human tumours, leads to anaphase bridge formation (in which sister chromatids are linked by catenated strands of DNA) and a G2/M-phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes interact directly with endogenous topoisomerase IIα (TOP2A) through BAF250a and are required for the binding of TOP2A to approximately 12,000 sites across the genome. Our results demonstrate that TOP2A chromatin binding is dependent on the ATPase activity of BRG1, which is compromised in oncogenic BRG1 mutants. These studies indicate that the ability of TOP2A to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumour suppressors.
    Keywords: Antigens, Neoplasm -- Metabolism ; DNA Helicases -- Metabolism ; DNA Topoisomerases, Type II -- Metabolism ; DNA, Catenated -- Chemistry ; DNA-Binding Proteins -- Metabolism ; Nuclear Proteins -- Metabolism ; Transcription Factors -- Metabolism;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Journal of Theoretical Biology, August 7, 2014, Vol.354, p.105(8)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtbi.2014.03.028 Byline: Joanna Kawka, Dominik Sturm, Sabrina Pleier, Stefan Pfister, Anna Marciniak-Czochra Abstract: Deregulation of signaling pathways and subsequent abnormal interactions of downstream genes very often results in carcinogenesis. In this paper, we propose a two-compartment model describing intricate dynamics of the target genes of the Wnt signaling pathway in medulloblastoma. The system of nine nonlinear ordinary differential equations accounts for the formation and dissociation of complexes as well as for the transcription, translation and transport between the cytoplasm and the nucleus. We focus on the interplay between MYC and SGK1 (serum and glucocorticoid-inducible kinase 1), which are the products of Wnt/[beta]-catenin signaling pathway, and GSK3[beta] (glycogen synthase kinase). Numerical simulations of the model solutions yield a better understanding of the process and indicate the importance of the SGK1 gene in the development of medulloblastoma, which has been confirmed in our recent experiments. The model is calibrated based on the gene expression microarray data for two types of medulloblastoma, characterized by monosomy and trisomy of chromosome 6q to highlight the difference between diagnoses. Author Affiliation: (a) Institute of Applied Mathematics, Interdisciplinary Center for Scientific Computing (IWR) and BIOQUANT, University of Heidelberg, Germany (b) Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany Article History: Received 2 September 2013; Revised 6 February 2014; Accepted 16 March 2014
    Keywords: Medulloblastoma -- Analysis ; Glucose Metabolism -- Analysis ; Deregulation -- Analysis ; Glucocorticoids -- Analysis ; Glycogen Synthesis -- Analysis ; Glycogen -- Analysis ; Gene Expression -- Analysis
    ISSN: 0022-5193
    Source: Cengage Learning, Inc.
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  • 4
    Language: English
    In: Cell, 24 April 2014, Vol.157(3), pp.525-527
    Description: Hierarchical cell state models, wherein a few stem-like tumor-propagating cells repopulate the tumor after therapy, are often invoked in cancer. Suvà et al. demonstrate a plastic developmental hierarchy in glioma cell populations by characterizing the epigenetic states of phenotypically distinct cells and identifying four factors sufficient to reprogram differentiated cells into a tumorigenic stem-like state.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 5
    Language: German
    In: Zeitschrift fuer Evidenz, Fortbildung und Qualitaet im Gesundheitswesen, 2011, Vol.105(7), pp.511-513
    Description: In den 1960er Jahren konnten weniger als fünf Prozent der Kinder, die an Krebs erkrankten, geheilt werden. Heute sind es etwa drei Viertel. Zu diesem Erfolg beigetragen hat die molekularbiologische Forschung, die dem Entstehen von Tumoren auf der Ebene der Zellen, Gene und Moleküle nachspürt. Zu ihren Resultaten zählen beispielsweise molekulare Marker, die bei Blutkrebserkrankungen voraussagen lassen, wie intensiv eine Behandlung erfolgen muss, um größtmöglichen Erfolg zu haben. Auch für Hirntumoren des Kindesalters konnten mittlerweile solche molekularen Marker identifiziert werden. Sie lassen auf eine individuellere, zielgerichtete Therapie hoffen. During the 1960s less than five percent of the children suffering from cancer could be cured. Today we are able to cure approximately three quarters. It is research in molecular biology elucidating the origin of cancer at the level of cells, genes and molecules that has accounted for this success. Research results include, for example, the identification of molecular markers of leukaemia that are able to predict the intensity of therapy necessary for maximum benefit. Furthermore, molecular markers have been identified for paediatric brain tumours which raise the hope for more individualized and targeted therapy.
    Keywords: Molekulare Marker ; Hirntumoren Des Kindesalters ; Medulloblastom ; Risikogruppen (Wie Vom Gastherausgeber Eingereicht) ; Molecular Marker ; Paediatric Brain Tumours ; Medulloblastoma ; Risk Stratification (As Supplied By Publisher) ; Medicine
    ISSN: 1865-9217
    E-ISSN: 2212-0289
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(4), p.e0124870
    Description: Medulloblastomas are malignant childhood brain tumors that arise due to the aberrant activity of developmental pathways during postnatal cerebellar development and in adult humans. Transcriptome analysis has identified four major medulloblastoma subgroups. One of them, the Sonic hedgehog (SHH) subgroup, is caused by aberrant Hedgehog signal transduction due to mutations in the Patched1 (PTCH1) receptor or downstream effectors. Mice carrying a Patched-1 null allele (Ptch1∆/+) are a good model to study the alterations underlying medulloblastoma development as a consequence of aberrant Hedgehog pathway activity.Transcriptome analysis of human medulloblastomas shows that SERPINE2, also called Protease Nexin-1 (PN-1) is overexpressed in most medulloblastomas, in particular in the SHH and WNT subgroups. As siRNA-mediated lowering of SERPINE2/PN-1 in human medulloblastoma DAOY cells reduces cell proliferation, we analyzed its potential involvement in medulloblastoma development using the Ptch1∆/+ mouse model. In Ptch1∆/+ mice, medulloblastomas arise as a consequence of aberrant Hedgehog pathway activity. Genetic reduction of Serpine2/Pn-1 interferes with medulloblastoma development in Ptch1∆/+ mice, as ~60% of the pre-neoplastic lesions (PNLs) fail to develop into medulloblastomas and remain as small cerebellar nodules. In particular the transcription factor Atoh1, whose expression is essential for development of SHH subgroup medulloblastomas is lost. Comparative molecular analysis reveals the distinct nature of the PNLs in young Ptch1∆/+Pn-1Δ/+ mice. The remaining wild-type Ptch1 allele escapes transcriptional silencing in most cases and the aberrant Hedgehog pathway activity is normalized. Furthermore, cell proliferation and the expression of the cell-cycle regulators Mycn and Cdk6 are significantly reduced in PNLs of Ptch1∆/+Pn-1Δ/+ mice.Our analysis provides genetic evidence that aberrant Serpine2/Pn-1 is required for proliferation of human and mouse medulloblastoma cells. In summary, our analysis shows that Serpine2/PN-1 boosts malignant progression of PNLs to medulloblastomas, in which the Hedgehog pathway is activated in a SHH ligand-independent manner.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    In: International Journal of Cancer, 01 February 2014, Vol.134(3), pp.703-716
    Description: Based on extensive pre‐clinical studies, the oncolytic parvovirus H‐1 (H‐1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high‐risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H‐1PV on MB cells and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non‐transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H‐1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H‐1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H‐1PV. H‐1PV induced down‐regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H‐1PV infection. H‐1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus. What's new? Medulloblastoma, the most frequent pediatric brain cancer, causes death in about 60 percent of high‐risk patients, and so there is a major need for novel, highly effective therapies. One therapy of interest is parvovirus H‐1 (H‐1PV), which was found in this study to produce marked cytotoxic effects in six medulloblastoma cell lines. Gene expression profiling revealed that H‐1PV infection causes down‐regulation of key regulatory genes involved in early neurogenesis, with significant repression of . The master regulators affected may represent putative direct or indirect H‐1PV target genes.
    Keywords: Medulloblastoma ; Oncolytic Virus ; Parvovirus H‐1pv ; Cellular Targets ; Myc ; Master Regulators Of Neurogenesis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 8
    In: International Journal of Cancer, 01 January 2014, Vol.134(1), pp.21-31
    Description: The canonical Sonic Hedgehog (Shh)/Gli pathway plays multiples roles during central nervous system (CNS) development. To elucidate the molecular repertoire of Shh mediators, we have recently described novel transcriptional targets in response to Shh pathway modulation. Among them, we were able to identify Neogenin1 (Neo1), a death dependence receptor, as a new direct Shh downstream regulator in neural precursor proliferation. As appropriate Shh signaling is required for cerebellar growth and alterations cause Shh‐driven medulloblastoma (MB), here we have addressed the role of the Shh/Neogenin1 interaction in the context of cerebellar development and cancer. We demonstrate that the Shh pathway regulates Neogenin1 expression in mouse models that recapitulate the Shh MB subtype. We show that the canonical Shh pathway directly regulates the gene acting through an upstream sequence in its promoter both and in granule neuron precursor cells. We also identified and characterized a functional Gli‐binding site in the first intron of the human gene. Gene expression profiling of more than 300 MB shows that is indeed upregulated in SHH tumors compared to the other MB subgroups. Finally, we provide evidence that NEO1 is necessary for cell cycle progression in a human MB cell line, because a loss of function of arrests cells in the G2/M phase. Taken together, these results highlight Neogenin1 as a novel downstream effector of the Shh pathway in MB and a possible therapeutic target. What's new? Abnormal activation of the canonical Sonic Hedgehog (Shh)/Gli pathway has been associated with up to 30% of the human cases of medulloblastoma, which represents the most common malignant primary brain tumor in children. A greater knowledge of the cellular response to Shh pathway activation in the cerebellum is critical for both understanding disease formation and developing new treatments. In this study, the authors identified Neogenin‐1 as a novel downstream effector of the Shh pathway that mediates proliferation in both cultured cerebellar progenitors and shh‐driven medulloblastoma. The data suggest that targeting Neogenin‐1 could offer a promising alternative to current anti‐medulloblastoma therapies.
    Keywords: Medulloblastoma ; Sonic Hedgehog ; Neogenin 1 ; Gli ; Cancer
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 9
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.LB-198-LB-198
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 10
    Language: English
    In: Journal of Theoretical Biology, 07 August 2014, Vol.354, pp.105-112
    Description: Deregulation of signaling pathways and subsequent abnormal interactions of downstream genes very often results in carcinogenesis. In this paper, we propose a two-compartment model describing intricate dynamics of the target genes of the Wnt signaling pathway in medulloblastoma. The system of nine nonlinear ordinary differential equations accounts for the formation and dissociation of complexes as well as for the transcription, translation and transport between the cytoplasm and the nucleus. We focus on the interplay between and (serum and glucocorticoid-inducible kinase 1), which are the products of Wnt/ -catenin signaling pathway, and (glycogen synthase kinase). Numerical simulations of the model solutions yield a better understanding of the process and indicate the importance of the gene in the development of medulloblastoma, which has been confirmed in our recent experiments. The model is calibrated based on the gene expression microarray data for two types of medulloblastoma, characterized by monosomy and trisomy of chromosome 6q to highlight the difference between diagnoses.
    Keywords: Myc ; Gsk3β ; Wnt Signaling Pathway ; Differential Equations ; Biology
    ISSN: 0022-5193
    E-ISSN: 1095-8541
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