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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
    In: Oncogene, 2016, Vol.35(32), p.4256-4268
    Description: Post-natal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for the SHH-associated subgroup of medulloblastoma (MB), is driven by Sonic Hedgehog (Shh) and Insulin-like Growth Factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is up-regulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh-subgroup of MB in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and medulloblastoma cells and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.
    Keywords: Article ; Medulloblastoma ; Sonic Hedgehog ; Hippo ; Yb1 ; Yap ; Igf2 ; Cerebellum ; Cell Cycle
    ISSN: 0950-9232
    E-ISSN: 1476-5594
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  • 8
    Language: English
    In: International Journal of Cancer, 01 November 2011, Vol.129(9), pp.2297-2303
    Description: Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated Ras/Raf/MEK/ERK signaling. Common genetic lesions observed in PA, which are linked to aberrant ERK pathway activity, include either inactivation, or gain‐of‐function mutations. To investigate the mutation spectrum within the proto‐oncogene encoding the Ser/Thr‐kinase B‐Raf in more detail, we analyzed 64 primary tumor samples from children with PA including two patients with neurofibromatosis type 1 (NF1). The well‐known mutation was found in 6/64 (9.38%) of our samples. For the first time, we report concomitant presence of a somatic mutation in an NF1 patient indicating that more than one Ras/ERK pathway component can be affected in PA. Furthermore, 2/64 (3.13%) of our samples carried a 3‐bp insertion in resulting in the duplication of threonine 599. This conserved residue is located within the activation segment and, if phosphorylated in a Ras‐dependent manner, plays a key role in Raf activation. Here, we demonstrate that this mutant (B‐Raf) and another B‐Raf mutant, which carries two additional threonine residues at this position, display an kinase activity and cellular MEK/ERK activation potential comparable to those of B‐Raf. Notably, replacement of threonines by valine residues had similar effects on B‐Raf activity, suggesting that the distortion of the peptide backbone by additional amino acids rather than the insertion of additional, potential phosphorylation sites destabilizes the inactive conformation of the kinase domain. We also demonstrate that B‐Raf and B‐Raf, but not B‐Raf, provoke drastic morphological alterations in human astrocytes.
    Keywords: Pilocytic Astrocytoma ; Neurofibromatosis Type 1 ; B‐Raf ; Insertion Mutagenesis ; Mapk Pathway
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 9
    Language: English
    In: Journal of Neuro-Oncology, 2014, Vol.118(2), pp.225-238
    Description: Primary brain tumors cumulatively represent the most common solid tumors of childhood and are the leading cause of cancer related death in this age group. Traditionally, molecular findings and histological analyses from biopsies of resected tumor tissue have been used for diagnosis and classification of these diseases. However, there is a dearth of useful biomarkers that have been validated and clinically implemented for pediatric brain tumors. Notably, diseases of the central nervous system (CNS) can be assayed through analysis of cerebrospinal fluid (CSF) and as such, CSF represents an appropriate medium to obtain liquid biopsies that can be informative for diagnosis, disease classification and risk stratification. Proteomic profiling of pediatric CNS malignancies has identified putative protein markers of disease, yet few effective biomarkers have been clinically validated or implemented. Advances in protein quantification techniques have made it possible to conduct such investigations rapidly and accurately through proteome-wide analyses. This review summarizes the current literature on proteomics in pediatric neuro-oncology and discusses the implications for clinical applications of proteomics research. We also outline strategies for translating effective CSF proteomic studies into clinical applications to optimize the care of this patient population.
    Keywords: Proteomics ; Cerebrospinal fluid (CSF) ; Pediatric ; Neuro-oncolgy ; Biomarker
    ISSN: 0167-594X
    E-ISSN: 1573-7373
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  • 10
    Language: English
    In: Nature neuroscience, September 2015, Vol.18(9), pp.1236-46
    Description: Over 20% of the drugs for treating human diseases target ion channels, but no cancer drug approved by the US Food and Drug Administration (FDA) is intended to target an ion channel. We found that the EAG2 (Ether-a-go-go 2) potassium channel has an evolutionarily conserved function for promoting brain tumor growth and metastasis, delineate downstream pathways, and uncover a mechanism for different potassium channels to functionally cooperate and regulate mitotic cell volume and tumor progression. EAG2 potassium channel was enriched at the trailing edge of migrating medulloblastoma (MB) cells to regulate local cell volume dynamics, thereby facilitating cell motility. We identified the FDA-approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings illustrate the potential of targeting ion channels in cancer treatment.
    Keywords: Evolution, Molecular ; Brain Neoplasms -- Drug Therapy ; Drug Delivery Systems -- Methods ; Ether-A-Go-Go Potassium Channels -- Antagonists & Inhibitors ; Thioridazine -- Administration & Dosage
    ISSN: 10976256
    E-ISSN: 1546-1726
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