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Berlin Brandenburg

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  • Tumors
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  • 1
    In: Neuro-Oncology, 2014, Vol. 16(suppl5), pp.v54-v54
    Description: During tumour progression, brain tumour cells are exposed to metabolic stress, such as nutrient deprivation, due to abnormal tumour vasculature. The ability of tumour cells to respond and manage reduced nutrient availability has a strong impact on tumour outcome. The molecular pathways supporting metabolic adaptation of brain tumour cells to nutrient stress represent potential therapeutic targets which are still not well defined. We report that the translation elongation factor 2 (eEF2) kinase mediates a protective response under nutrient starvation by restraining mRNA translation at the step of elongation. In aggressive human tumour cells, such as medulloblastoma (MB) cells, ablation of eEF2K expression increases sensitivity to nutrient removal. In addition, gene expression analysis in patient samples show that eEF2K expression is upregulated in the most aggressive subgroup of MB, namely group 3, and that high eEF2K expression is strongly associated with poor survival in both MB and glioblastoma (GBM). In vivo, eEF2K overexpression confers resistance of tumour xenografts to calorie restriction. Finally, our data reveal that eEF2K is an evolutionarily conserved mediator of the physiological response to nutrient starvation, as genetic removal of eEF2K compromises survival of C. elegans in absence of nutrients. Overall, our works highlight a novel pro-survival factor which is hijacked by brain tumour cells to support their adaptation to nutrient stress. The potential for therapeutic targeting of eEF2 kinase in brain tumors will be discussed.
    Keywords: Starvation ; Glioblastoma ; Adaptations ; Data Processing ; Translation Elongation Factor 2 ; Nutrient Availability ; Stress ; Oncology ; Nutrients ; Tumors ; Brain Tumors ; Gene Expression ; Nutrient Deficiency ; Medulloblastoma ; Xenografts ; Evolution ; Neurology & Neuropathology;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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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
    Language: English
    In: He, X., L. Zhang, Y. Chen, M. Remke, D. Shih, F. Lu, H. Wang, et al. 2014. “The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma.” Nature medicine 20 (9): 1035-1042. doi:10.1038/nm.3666. http://dx.doi.org/10.1038/nm.3666.
    Description: Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G-protein Gsα, as a potent tumor suppressor gene that defines a subset of aggressive Sonic Hedgehog (Shh)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically-distinct progenitors is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gsα is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh-signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas mutants. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gsα that acts as a molecular link across Shh-group medulloblastomas of disparate cellular and anatomical origins, illuminating G-protein modulation as a potential therapeutic avenue.
    Keywords: Medulloblastoma ; G-Protein ; Camp ; Gpcr ; Cell Lineage ; Sonic Hedgehog Signaling ; Cilia ; Cellular Origins
    ISSN: 1078-8956
    E-ISSN: 1546170X
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  • 4
    In: Nature Genetics, 2013, Vol.46(1), p.39
    Description: Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC(1,2). We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter (3) that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B (4,5). Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform.
    Keywords: Microrna -- Physiological Aspects ; Microrna -- Genetic Aspects ; Microrna -- Research ; Brain Tumors -- Risk Factors ; Brain Tumors -- Genetic Aspects ; Brain Tumors -- Research ; Gene Expression -- Physiological Aspects ; Gene Expression -- Research ; Methyltransferases -- Physiological Aspects ; Methyltransferases -- Genetic Aspects ; Methyltransferases -- Research;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 5
    In: STEM CELLS, January 2014, Vol.32(1), pp.244-257
    Description: Data from transgenic mouse models show that neuronal progenitor cells (NPCs) migrate toward experimental brain tumors and modulate the course of pathology. However, the pathways whereby NPCs are attracted to CNS neoplasms are not fully understood and it is unexplored if NPCs migrate toward brain tumors (high‐grade astrocytomas) in humans. We analyzed the tumor‐parenchyma interface of neurosurgical resections for the presence of (NPCs) and distinguished these physiological cells from the tumor mass. We observed that polysialic acid neural cell adhesion molecule‐positive NPCs accumulate at the border of high‐grade astrocytomas and display a marker profile consistent with immature migratory NPCs. Importantly, these high‐grade astrocytoma‐associated NPCs did not carry genetic aberrations that are indicative of the tumor. Additionally, we observed NPCs accumulating in CNS metastases. These metastatic tumors are distinguished from neural cells by defined sets of markers. Transplanting murine glioma cells embedded in a cell‐impermeable hollow fiber capsule into the brains of nestin‐gfp reporter mice showed that diffusible factors are sufficient to induce a neurogenic reaction. In vitro, vascular endothelial growth factor (VEGF) secreted from glioma cells increases the migratory and proliferative behavior of adult human brain‐derived neural stem and progenitor cells via stimulation of VEGF receptor‐2 (VEGFR‐2). In vivo, inhibiting VEGFR‐2 signaling with a function‐blocking antibody led to a reduction in NPC migration toward tumors. Overall, our data reveal a mechanism by which NPCs are attracted to CNS tumors and suggest that NPCs accumulate in human high‐grade astrocytomas. S C
    Keywords: Glioma ; Psa‐Ncam ; Neuronal Progenitor ; Beta Iii‐Tubulin Protein ; Human
    ISSN: 1066-5099
    E-ISSN: 1549-4918
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  • 6
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 August 2015, Vol.21(16), pp.3750-8
    Description: Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production. At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.
    Keywords: DNA Copy Number Variations -- Genetics ; Ependymoma -- Genetics ; Spinal Neoplasms -- Genetics ; Transcriptome -- Genetics
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 7
    Language: English
    In: Cell, 23 May 2013, Vol.153(5), pp.1064-1079
    Description: Metabolic adaptation is essential for cell survival during nutrient deprivation. We report that eukaryotic elongation factor 2 kinase (eEF2K), which is activated by AMP-kinase (AMPK), confers cell survival under acute nutrient depletion by blocking translation elongation. Tumor cells exploit this pathway to adapt to nutrient deprivation by reactivating the AMPK-eEF2K axis. Adaptation of transformed cells to nutrient withdrawal is severely compromised in cells lacking eEF2K. Moreover, eEF2K knockdown restored sensitivity to acute nutrient deprivation in highly resistant human tumor cell lines. In vivo, overexpression of eEF2K rendered murine tumors remarkably resistant to caloric restriction. Expression of strongly correlated with overall survival in human medulloblastoma and glioblastoma multiforme. Finally, strains deficient in , the ortholog, were severely compromised in their response to nutrient depletion. Our data highlight a conserved role for eEF2K in protecting cells from nutrient deprivation and in conferring tumor cell adaptation to metabolic stress. Tumor cells adapt to the stress of nutrient deprivation by increasing the activity of translation elongation factor 2 kinase (eEF2K), which protects cells from apoptosis by inhibiting the elongation step of mRNA translation.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 8
    Language: English
    In: Acta Neuropathologica, 2012, Vol.123(4), pp.615-626
    Description: The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r  = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials.
    Keywords: Medulloblastoma ; Molecular classification ; Clinical trials ; NanoString
    ISSN: 0001-6322
    E-ISSN: 1432-0533
    Source: Springer Science & Business Media B.V.
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  • 9
    Language: English
    In: Acta Neuropathologica, 2012, Vol.123(4), pp.465-472
    Description: Medulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratification include clinical factors (age, presence of metastases, and extent of resection) as well as histological subgrouping (classic, desmoplastic, and large cell/anaplastic histology). Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes. Variations in the number, composition, and nature of the subgroups between studies brought about a consensus conference in Boston in the fall of 2010. Discussants at the conference came to a consensus that the evidence supported the existence of four main subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). Participants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups.
    Keywords: Medulloblastoma ; Consensus ; Subgroups ; SHH ; WNT ; Group 3 ; Group 4
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 10
    Language: English
    In: Journal of Photochemistry & Photobiology, B: Biology, December 2018, Vol.189, pp.298-305
    Description: Medulloblastoma (MB) is the most common malignant primary brain tumor of childhood. High risk patients still have a poor outcome, and especially young patients suffer from standard therapy induced sequelae. Therefore, other therapeutic options need to be explored. In glioblastoma (GBM), application of 5-aminolaevulinic acid (5-ALA) results in selective accumulation of protoporphyrin IX (PPIX) in the tumor cells, which can be exploited during fluorescence-guided surgery to increase the extent of resection or for photodynamic therapy (PDT) induced phototoxicity. It is not entirely clear, whether MB cells accumulate PPIX and are sensitive to PDT. Human -amplified (Med8A and D283) and non-amplified (UW228–2 and ONS76) MB cell lines were incubated for 2, 4 or 6 h with increasing doses (0–100 μg/ml) of 5-ALA, and PPIX accumulation was determined by flow cytometry. To assess sensitivity to 5-ALA/PDT, cells were incubated with 5-ALA and subsequently exposed to laser light of 635 nm wavelength (18.75 J/cm ). After an additional 24 h culture period, viability of cells was quantified using the WST-1 assay. Expression of ferrochelatase was detected by reverse transcription and quantitative polymerase chain reaction. Ferrochelatase activity was quantified by measuring the enzymatic conversion of PPIX to zinc-protoporphyrin. Expression of the ABCG2 transporter protein CD338 was detected by flow cytometry. All MB cell lines showed a time- and dose-dependent accumulation of PPIX after exposure to exogenous 5-ALA and became sensitive to 5-ALA/PDT-induced phototoxicity. PPIX accumulation was reduced compared to U373 GBM cells at shorter incubation periods and limiting 5-ALA doses. Moreover, not all MB cells became PPIX positive and overall phototoxicity was lower in the MB cell lines. Notably, the -amplified MB cells demonstrated a more pronounced photosensitivity compared to their non-amplified counterparts. There was no difference in expression of ferrochelatase, but enzymatic activity appeared to be reduced in the MB cells compared to U373 GBM cells, whereas CD338 was expressed on the MB cells only. Medulloblastoma cell lines accumulate PPIX after application of 5-ALA and become sensitive to PDT, associated with low ferrochelatase expression and activity. Photosensitivity is more pronounced in -amplified cell lines. In contrast to GBM cells, however, PPIX accumulation appears to be reduced, restricted to a subset of cells and associated with lower photosensitivity of the MB cell lines, possibly due to expression of the ABCG2 transporter protein CD338 on MB cells.
    Keywords: 5-ALA ; Medulloblastoma ; Pdt ; Photodiagnosis ; Ferrochelatase ; Abcg2 ; Biology ; Chemistry
    ISSN: 1011-1344
    E-ISSN: 1873-2682
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