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  • Elsevier (CrossRef)  (21)
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  • 1
    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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  • 2
    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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  • 3
    Language: English
    In: Cell Reports, 29 March 2016, Vol.14(12), pp.2925-2937
    Description: How brain tumors progress from precancerous lesions to advanced cancers is not well understood. Using mice to study medulloblastoma progression, we found that loss of heterozygosity (LOH) is an early event that is associated with high levels of cell senescence in preneoplasia. In contrast, advanced tumors have evaded senescence. Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic mutations or locus inactivation. Consistent with senescence evasion, these mutations are always subsequent to LOH. Introduction of a mutation prevents senescence, accelerates tumor formation, and increases medulloblastoma incidence. Altogether, our results show that evasion of senescence associated with LOH allows progression to advanced tumors. How brain tumors develop from precancerous lesions is not well understood. Using heterozygous mice, Tamayo-Orrego et al. show that medulloblastoma preneoplastic lesions display loss of heterozygosity and cell senescence, a tumor-suppressive mechanism. Subsequently, spontaneous mutations or inactivation leads to senescence evasion and medulloblastoma progression.
    Keywords: Medulloblastoma ; Sonic Hedgehog ; Ptch1 ; Preneoplasia ; Cerebellum ; P53 ; P16ink4a ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 4
    Language: English
    In: Cell, 20 January 2012, Vol.148(1-2), pp.59-71
    Description: Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. ► Complex chromosomal alterations (chromothripsis) observed in medulloblastomas ► Cancers with such alterations harbor TP53 mutations ► Context-specific link between the status of p53 and likelihood of chromothripsis ► p53 status and chromothripsis also correlate with aggressive acute myeloid leukemia Connecting p53 status and chromothripsis in specific types of cancer provides a genetic basis for the more aggressive forms of medulloblastoma and leukemia.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 5
    Language: English
    In: Developmental Cell, 13 October 2014, Vol.31(1), pp.34-47
    Description: During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that is upregulated in medulloblastomas and induces GCP proliferation. Conversely, inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression. Aberrant activation of Shh signaling leads to medulloblastoma. Mille, Tamayo-Orrego, Lévesque, et al. find that the Shh receptor Boc, through elevated Shh signaling, promotes high levels of DNA damage. This increases the incidence of loss of heterozygosity, leading to the progression from preneoplastic lesions to advanced medulloblastoma.
    Keywords: Biology
    ISSN: 1534-5807
    E-ISSN: 1878-1551
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  • 6
    Language: English
    In: Developmental Cell, 23 June 2014, Vol.29(6), pp.649-661
    Description: Signaling networks controlled by Sonic hedgehog (SHH) and the transcription factor Atoh1 regulate the proliferation and differentiation of cerebellar granule neuron progenitors (GNPs). Deregulations in those developmental processes lead to medulloblastoma formation, the most common malignant brain tumor in childhood. Although the protein Atoh1 is a key factor during both cerebellar development and medulloblastoma formation, up-to-date detailed mechanisms underlying its function and regulation have remained poorly understood. Here, we report that SHH regulates Atoh1 stability by preventing its phosphodependent degradation by the E3 ubiquitin ligase Huwe1. Our results reveal that SHH and Atoh1 contribute to a positive autoregulatory loop promoting neuronal precursor expansion. Consequently, Huwe1 loss in mouse SHH medulloblastoma illustrates the disruption of this developmental mechanism in cancer. Hence, the crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a collaborative network that could be further targeted in medulloblastoma. Signaling networks controlled by Sonic hedgehog (SHH) and the transcription factor Atoh1 control proliferation and differentiation in cerebellar development. Forget, Bihannic, et al. report that SHH regulates Atoh1 stability by preventing its phosphodependent degradation by the ubiquitin ligase Huwe1. Disruptions of this mechanism are later seen in SHH medulloblastoma.
    Keywords: Biology
    ISSN: 1534-5807
    E-ISSN: 1878-1551
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  • 7
    Language: English
    In: Cancer Letters, 28 August 2018, Vol.430, pp.34-46
    Description: Targeting of oncogene-driven replicative stress as therapeutic option for high-risk medullobastoma was assessed using a panel of medulloblastoma cells differing in their c-Myc expression [i.e. group SHH (c-Myc low) vs. group 3 (c-Myc high)]. High c-Myc levels were associated with hypersensitivity to pharmacological Chk1 and ATR inhibition but not to CDK inhibition nor to conventional (genotoxic) anticancer therapeutics. The enhanced sensitivity of group 3 medulloblastoma cells to Chk1 inhibitors likely results from enhanced damage to intracellular organelles, elevated replicative stress and DNA damage and activation of apoptosis/necrosis. Furthermore, Chk1 inhibition differentially affected c-Myc expression and functions. In c-Myc high cells, Chk1 blockage decreased c-Myc and p-GSK3α protein and increased p21 and GADD45A mRNA expression. By contrast, c-Myc low cells revealed increased p-GSK3β protein and CHOP and DUSP1 mRNA levels. Inhibition of Chk1 sensitized medulloblastoma cells to additional replication stress evoked by cisplatin independent of c-Myc. Importantly, Chk1 inhibition only caused minor toxicity in primary rat neurons . Collectively, targeting of ATR/Chk1 effectively triggers death in high-risk medulloblastoma, potentiates the anticancer efficacy of cisplatin and is well tolerated in non-cancerous neuronal cells.
    Keywords: Checkpoint Kinase ; DNA Damage Response ; DNA Repair ; Medulloblastoma ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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  • 8
    Language: English
    In: The American Journal of Pathology, December 2018, Vol.188(12), pp.2902-2911
    Description: Patient-derived xenografts retain the genotype of the parent tumors more readily than tumor cells maintained in culture. The two previously reported clival chordoma xenografts were derived from recurrent tumors after radiation. To study the genetics of clival chordoma in the absence of prior radiation exposure we established a patient-derived xenograft at primary resection of a clival chordoma. Epicranial grafting of clival chordoma collected during surgery was performed. Tumor growth was established in a nonobese diabetic/severe combined immunodeficiency mouse and tumors have been passaged serially for seven generations. Physaliferous cell architecture was shown in the regenerated tumors, which stained positive for Brachyury, cytokeratin, and S100 protein. The tumors showed bone invasion. Single-nucleotide polymorphism analysis of the tumor xenograft was compared with the parental tumor. Copy number gain of the gene ( ) and heterozygous loss of cyclin dependent kinase inhibitor 2A ( ) was observed. Heterozygous loss of the tumor-suppressor fragile histidine triad ( ) gene also was observed, although protein expression was preserved. Accumulation of copy number losses and gains as well as increased growth rate was observed over three generations. The patient-derived xenograft reproduces the phenotype of clival chordoma. This model can be used in the future to study chordoma biology and to assess novel treatments.
    Keywords: Medicine
    ISSN: 0002-9440
    E-ISSN: 1525-2191
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  • 9
    Language: English
    In: Cell, 25 February 2016, Vol.164(5), pp.1060-1072
    Description: Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated “CNS neuroblastoma with activation (CNS NB- ),” “CNS Ewing sarcoma family tumor with alteration (CNS EFT- ),” “CNS high-grade neuroepithelial tumor with alteration (CNS HGNET- ),” and “CNS high-grade neuroepithelial tumor with alteration (CNS HGNET- ),” will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. Highly malignant primitive neuroectodermal tumors of the CNS (CNS-PNETs) have been challenging to diagnose and distinguish from other kinds of brain tumors, but molecular profiling now reveals that these cancers can be readily classified into some known tumor types and four new entities with distinct histopathological and clinical features, paving the way for meaningful clinical trials.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 10
    Language: English
    In: The American Journal of Pathology, November 2012, Vol.181(5), pp.1762-1772
    Description: Musashi1 (Msi1) is a highly conserved RNA-binding protein that is required during the development of the nervous system. Msi1 has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation, and has also been implicated in tumorigenesis, being highly expressed in multiple tumor types. We analyzed Msi1 expression in a large cohort of medulloblastoma samples and found that Msi1 is highly expressed in tumor tissue compared with normal cerebellum. Notably, high Msi1 expression levels proved to be a sign of poor prognosis. Msi1 expression was determined to be particularly high in molecular subgroups 3 and 4 of medulloblastoma. We determined that Msi1 is required for tumorigenesis because inhibition of Msi1 expression by small-interfering RNAs reduced the growth of Daoy medulloblastoma cells in xenografts. To characterize the participation of Msi1 in medulloblastoma, we conducted different high-throughput analyses. Ribonucleoprotein immunoprecipitation followed by microarray analysis (RIP-chip) was used to identify mRNA species preferentially associated with Msi1 protein in Daoy cells. We also used cluster analysis to identify genes with similar or opposite expression patterns to Msi1 in our medulloblastoma cohort. A network study identified RAC1, CTGF, SDCBP, SRC, PRL, and SHC1 as major nodes of an Msi1-associated network. Our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target.
    Keywords: Medicine
    ISSN: 0002-9440
    E-ISSN: 1525-2191
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