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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 27 March 2018, Vol.115(13), pp.3392-3397
    Description: The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location because SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened () mutations form more specifically in the hemispheres than those with Patched 1 () mutations. Using sporadic mouse models of SHH-MB with the two mutations commonly seen in adult MB, constitutive activation of () or loss-of-, we found that regardless of timing of induction or type of mutation, tumors developed primarily in the hemispheres, with -mutants indeed showing a stronger specificity. We further uncovered that GCPs in the hemispheres are more susceptible to high-level SHH signaling compared with GCPs in the medial cerebellum (vermis), as more or -mutant hemisphere cells remain undifferentiated and show increased tumorigenicity when transplanted. Finally, we identified location-specific GCP gene-expression profiles, and found that deletion of the genes most highly expressed in the hemispheres () or vermis (Engrailed1) showed opposing effects on GCP differentiation. Our studies thus provide insights into intrinsic differences within GCPs that impact on SHH-MB progression.
    Keywords: En1 ; Mri ; Nr2f2 ; Cerebellar Hemispheres ; Granule Cell Precursors ; Cerebellar Neoplasms -- Pathology ; Cerebellum -- Pathology ; Hedgehog Proteins -- Metabolism ; Medulloblastoma -- Pathology ; Patched-1 Receptor -- Metabolism ; Smoothened Receptor -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature Medicine, 2014, Vol.20(12), p.1378
    Description: Despite advances in chemotherapy and radiation over the past 40 years, the outcome for children with diffuse intrinsic pontine gliomas (DIPGs) remains almost uniformly fatal, with survival of less than 12 months despite numerous trials of chemotherapy, targeted agents and radiation therapy. Recently, large genome-sequencing studies of pediatric high-grade gliomas have been carried out and have consistently identified a lysine to methionine (K27M) substitution in histones H3.1 and H3.3 in over 80% of midline high-grade gliomas and DIPGs2.
    Keywords: Tumors ; Chemotherapy ; Radiation Therapy ; Medical Research ; Epigenetics;
    ISSN: 1078-8956
    E-ISSN: 1546170X
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  • 3
    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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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 12 November 2013, Vol.110(46), pp.E4325-34
    Description: The Sleeping Beauty (SB) transposon mutagenesis screen is a powerful tool to facilitate the discovery of cancer genes that drive tumorigenesis in mouse models. In this study, we sought to identify genes that functionally cooperate with sonic hedgehog signaling to initiate medulloblastoma (MB), a tumor of the cerebellum. By combining SB mutagenesis with Patched1 heterozygous mice (Ptch1(lacZ/+)), we observed an increased frequency of MB and decreased tumor-free survival compared with Ptch1(lacZ/+) controls. From an analysis of 85 tumors, we identified 77 common insertion sites that map to 56 genes potentially driving increased tumorigenesis. The common insertion site genes identified in the mutagenesis screen were mapped to human orthologs, which were used to select probes and corresponding expression data from an independent set of previously described human MB samples, and surprisingly were capable of accurately clustering known molecular subgroups of MB, thereby defining common regulatory networks underlying all forms of MB irrespective of subgroup. We performed a network analysis to discover the likely mechanisms of action of subnetworks and used an in vivo model to confirm a role for a highly ranked candidate gene, Nfia, in promoting MB formation. Our analysis implicates candidate cancer genes in the deregulation of apoptosis and translational elongation, and reveals a strong signature of transcriptional regulation that will have broad impact on expression programs in MB. These networks provide functional insights into the complex biology of human MB and identify potential avenues for intervention common to all clinical subgroups.
    Keywords: Gene Regulatory Networks -- Genetics ; Hedgehog Proteins -- Metabolism ; Medulloblastoma -- Genetics ; Nfi Transcription Factors -- Genetics ; Signal Transduction -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 5
    In: Nature, 2014
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Keywords: Medulloblastoma – Research ; Medulloblastoma – Health Aspects ; DNA Sequencing – Analysis ; Growth Factor Receptors – Analysis;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 6
    Language: English
    In: The Journal of clinical investigation, April 2011, Vol.121(4), pp.1344-8
    Description: Pilocytic astrocytoma (PA) is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. Children with incompletely resected PA represent a clinically challenging patient cohort for whom conventional adjuvant therapies are only moderately effective. This has produced high clinical demand for testing of new molecularly targeted treatments. However, the development of new therapeutics for PA has been hampered by the lack of an adequate in vivo tumor model. Recent studies have identified activation of MAPK signaling, mainly by oncogenic BRAF activation, as a hallmark genetic event in the pathogenesis of human PA. Using in vivo retroviral somatic gene transfer into mouse neural progenitor cells, we have shown here that ectopic expression of the activated BRAF kinase domain is sufficient to induce PA in mice. Further in vitro analyses demonstrated that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with the kinase inhibitor sorafenib. Our in vivo model for PA shows that the activated BRAF kinase domain is sufficient to induce PA and highlights its role as a potential therapeutic target.
    Keywords: Astrocytoma -- Etiology ; Brain Neoplasms -- Etiology ; Proto-Oncogene Proteins B-Raf -- Genetics
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 7
    Language: English
    In: Nature Reviews Clinical Oncology, Nov, 2018, Vol.15(11), p.659
    Description: Comprehensive molecular characterization of infant medulloblastoma has uncovered the high degree of heterogeneity of this disease. Recent results from the SJYC07 study elegantly reveal that risk stratification can be improved if DNA methylation profiling data are incorporated into...
    Keywords: Molecular Diagnostic Techniques -- Innovations ; Gene Expression -- Health Aspects ; Pediatric Tumors -- Genetic Aspects ; Pediatric Tumors -- Development And Progression ; Pediatric Tumors -- Care And Treatment ; Medulloblastoma -- Care And Treatment ; Medulloblastoma -- Development And Progression ; Medulloblastoma -- Genetic Aspects
    ISSN: 1759-4774
    E-ISSN: 17594782
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  • 8
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 June 2010, Vol.16(12), pp.3240-52
    Description: Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. This study investigated the expression levels of individual human HDAC family members in primary medulloblastoma samples, their potential as risk stratification markers, and their roles in tumor cell growth. Gene expression arrays were used to screen for HDAC1 through HDAC11. Using quantitative real time reverse transcriptase-PCR and immunohistochemistry, we studied the expression of HDAC5 and HDAC9 in primary medulloblastoma samples. In addition, we conducted functional studies using siRNA-mediated knockdown of HDAC5 and HDAC9 in medulloblastoma cells. HDAC5 and HDAC9 showed the highest expression in prognostically poor subgroups. This finding was validated in an independent set of medulloblastoma samples. High HDAC5 and HDAC9 expression was significantly associated with poor overall survival, with high HDAC5 and HDAC9 expression posing an independent risk factor. Immunohistochemistry revealed a strong expression of HDAC5 and HDAC9 proteins in most of all primary medulloblastomas investigated. siRNA-mediated knockdown of HDAC5 or HDAC9 in medulloblastoma cells resulted in decreased cell growth and cell viability. HDAC5 and HDAC9 are significantly upregulated in high-risk medulloblastoma in comparison with low-risk medulloblastoma, and their expression is associated with poor survival. Thus, HDAC5 and HDAC9 may be valuable markers for risk stratification. Because our functional studies point toward a role in medulloblastoma cell growth, HDAC5 and HDAC9 may potentially be novel drug targets.
    Keywords: Biomarkers, Tumor -- Metabolism ; Brain Neoplasms -- Metabolism ; Histone Deacetylases -- Metabolism ; Medulloblastoma -- Metabolism ; Repressor Proteins -- Metabolism
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 9
    In: Current Opinion in Oncology, 2013, Vol.25(6), pp.674-681
    Description: PURPOSE OF REVIEW: The advent of integrated genomics revealed profound insights into medulloblastoma pathogenesis. However, these biological findings have yet to be translated into the clinic, as current treatment comprises surgical resection, conventional irradiation, and chemotherapy resulting in significant long-term sequelae. We sought to highlight the potential areas for targeted therapy based on our new understanding of the subgroup-specific tumor biology. RECENT FINDINGS: Recently, four distinct molecular subgroups of medulloblastoma have been identified [WNT (wingless), SHH (sonic hedgehog), Group 3, and Group 4]. Profiling of these subgroups revealed distinct genomic events, several of which represent actionable targets for therapy. Specifically, stratification of patients into their respective subgroups has profound prognostic impact, wherein therapy can be de-escalated in patients with favorable prognosis, and intensified therapy or novel agents can be considered in patients with poor prognosis. Novel subgroup-specific therapies are being explored in clinical trials, particularly for the SHH subgroup. Epigenetic modifiers are also recurrently affected in medulloblastoma suggesting that epigenetic therapy can be considered in a subset of patients. SUMMARY: The identification of subgroup-specific, actionable therapeutic targets has the potential to revolutionize therapy for medulloblastoma patients, and result in significantly improved quality of life in survivors and improved overall survival.
    Keywords: Adolescent–Genetics ; Adult–Metabolism ; Biomarkers, Tumor–Metabolism ; Cerebellar Neoplasms–Genetics ; Child–Metabolism ; Child, Preschool–Trends ; Disease-Free Survival–Genetics ; Epigenomics–Metabolism ; Female–Genetics ; Gene Expression Profiling–Metabolism ; Hedgehog Proteins–Metabolism ; Humans–Metabolism ; Male–Metabolism ; Medulloblastoma–Metabolism ; Molecular Targeted Therapy–Metabolism ; Mutation–Metabolism ; Prognosis–Metabolism ; Quality of Life–Metabolism ; RNA, Messenger–Metabolism ; Signal Transduction–Metabolism ; Survival Analysis–Metabolism ; Wnt Proteins–Metabolism ; Biomarkers, Tumor ; Hedgehog Proteins ; RNA, Messenger ; Shh Protein, Human ; Wnt Proteins;
    ISSN: 1040-8746
    E-ISSN: 1531703X
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  • 10
    Language: English
    In: Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 2014, Vol.30(6), pp.979-990
    Description: To describe how the quality of life (QOL) discussion in childhood medulloblastoma (MB) relates to treatment developments, survival and sequelae from 1920 to 2014. Articles containing "childhood medulloblastoma" and "quality of life" were identified in PubMed. Those containing phrases pertaining to psychological,...
    Keywords: Cancer Och Onkologi ; Cancer And Oncology ; Pediatrik ; Pediatrics ; Medulloblastoma; Surgery; Radiotherapy; Chemotherapy; Molecular Biology; Anesthesiology; Quality Of Life; Review
    ISSN: 1433-0350
    ISSN: 02567040
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