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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: 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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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    Language: English
    In: Blood, 19 July 2018, Vol.132(3), pp.307-320
    Description: Heat shock protein 90 (HSP90) stabilizes many client proteins, including the BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of chronic myeloid leukemia (CML) in which treatment-free remission (TFR) is limited, with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics that synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain of HSP90 are under investigation, but side effects such as induction of the heat shock response (HSR) and toxicity have so far precluded their US Food and Drug Administration approval. We have developed a novel inhibitor (aminoxyrone [AX]) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain. This was achieved by structure-based molecular design, chemical synthesis, and functional preclinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. AX is a promising potential candidate that induces apoptosis in the leukemic stem cell fraction (CD34CD38) as well as the leukemic bulk (CD34CD38) of primary CML and in tyrosine kinase inhibitor (TKI)-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated, and targeting the HSP90 C terminus by AX does not induce the HSR in vitro and in vivo. We also probed the potential of AX in other therapy-refractory leukemias. Therefore, AX is the first peptidomimetic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI-sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other types of therapy-refractory leukemia because of its low toxicity profile and lack of HSR.
    Keywords: Animals–Chemistry ; Antineoplastic Agents–Pharmacology ; Binding Sites–Drug Effects ; Biomarkers, Tumor–Drug Effects ; Cell Cycle–Drug Effects ; Cell Line, Tumor–Antagonists & Inhibitors ; Cell Survival–Chemistry ; Disease Models, Animal–Antagonists & Inhibitors ; Drug Resistance, Neoplasm–Chemistry ; Fusion Proteins, Bcr-Abl–Metabolism ; Hsp90 Heat-Shock Proteins–Drug Effects ; Heat-Shock Response–Chemistry ; Humans–Pharmacology ; Imatinib Mesylate–Drug Therapy ; Leukemia, Myelogenous, Chronic, BCR-Abl Positive–Metabolism ; Mice–Chemistry ; Models, Molecular–Pharmacology ; Molecular Conformation–Drug Effects ; Molecular Structure–Drug Effects ; Protein Binding–Drug Effects ; Protein Interaction Domains and Motifs–Drug Effects ; Protein Kinase Inhibitors–Drug Effects ; Protein Multimerization–Drug Effects ; Spectrum Analysis–Drug Effects ; Structure-Activity Relationship–Drug Effects ; Xenograft Model Antitumor Assays–Drug Effects ; Abridged ; Antineoplastic Agents ; Biomarkers, Tumor ; Hsp90 Heat-Shock Proteins ; Protein Kinase Inhibitors ; Imatinib Mesylate ; Fusion Proteins, Bcr-Abl;
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 7
    Language: English
    In: Cancer research, 01 January 2015, Vol.75(1), pp.134-46
    Description: Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)-driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood-brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven medulloblastoma.
    Keywords: Anilides -- Pharmacology ; Cerebellar Neoplasms -- Drug Therapy ; Hedgehog Proteins -- Metabolism ; Medulloblastoma -- Drug Therapy ; Quinolines -- Pharmacology
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 8
    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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  • 9
    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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  • 10
    In: Brain, 2018, Vol. 141(5), pp.1300-1319
    Description: The molecular events underlying dissemination of group 3 medulloblastoma remain elusive. Ferrucci et al. show that PRUNE1 overexpression enhances the canonical TGF-β cascade, upregulates OTX2 and SNAIL, and inhibits the tumour suppressor PTEN. They describe anti-metastatic properties of an anti-PRUNE1 drug, and identify further deleterious gene variants as therapeutic targets. Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL ( SNAI1 ) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common ‘non-synonymous homozygous’ deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3. 10.1093/brain/awy039_video1 awy039media1 5742053534001
    Keywords: Medulloblastoma ; Metastatic Cns Tumour ; Molecular Genetics ; Genetic Network ; Oncology
    ISSN: 0006-8950
    E-ISSN: 1460-2156
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