In vitro models of medulloblastoma: Choosing the right tool for the job

Ivanov, Delyan P.; Coyle, Beth; Walker, David; Grabowska, Anna

doi:10.1016/j.jbiotec.2016.07.028

Cited by 182 publications

(178 citation statements)

References 167 publications

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“…In contrast to the well-characterized WNT and SHH tumours, the main oncogenic drivers of Group 3 and Group 4 remains to be identified. Although several human cell lines for Group 3 medulloblastoma have been characterized, only few experimental in vivo models have been presented of Group 3 and Group 41516. Group 3 tumours harbour few recurrent mutations, but display structural genomic rearrangements ( e.g.…”

mentioning

confidence: 99%

Establishment and characterization of an orthotopic patient-derived Group 3 medulloblastoma model for preclinical drug evaluation

Sandén

Dyberg

Krona

et al. 2017

Sci Rep

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Medulloblastomas comprise a heterogeneous group of tumours and can be subdivided into four molecular subgroups (WNT, SHH, Group 3 and Group 4) with distinct prognosis, biological behaviour and implications for targeted therapies. Few experimental models exist of the aggressive and poorly characterized Group 3 tumours. In order to establish a reproducible transplantable Group 3 medulloblastoma model for preclinical therapeutic studies, we acquired a patient-derived tumour sphere culture and inoculated low-passage spheres into the cerebellums of NOD-scid mice. Mice developed symptoms of brain tumours with a latency of 17–18 weeks. Neurosphere cultures were re-established and serially transplanted for 3 generations, with a negative correlation between tumour latency and numbers of injected cells. Xenografts replicated the phenotype of the primary tumour, including high degree of clustering in DNA methylation analysis, high proliferation, expression of tumour markers, MYC amplification and elevated MYC expression, and sensitivity to the MYC inhibitor JQ1. Xenografts maintained maintained expression of tumour-derived VEGFA and stromal-derived COX-2. VEGFA, COX-2 and c-Myc are highly expressed in Group 3 compared to other medulloblastoma subgroups, suggesting that these molecules are relevant therapeutic targets in Group 3 medulloblastoma.

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mentioning

confidence: 99%

Establishment and characterization of an orthotopic patient-derived Group 3 medulloblastoma model for preclinical drug evaluation

Sandén

Dyberg

Krona

et al. 2017

Sci Rep

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“…S6A; refs. 48,49). MELK interacts with EZH2 in Daoy and MB25550 CSCs, and the xenografts that develop from the two kinds of MBSCs are strongly attenuated by RNA knockdown or inhibitors.…”

Section: Discussionmentioning

confidence: 99%

MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation

Liu

Sun

et al. 2017

Molecular Cancer Research

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Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stemlike cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma. In human medulloblastoma, extensive nodularity and large-cell/anaplastic subgroups differed according to the staining levels of MELK and EZH2 from the other two subgroups. The proportion of MELK-or EZH2-positive staining status could be considered as a potential indicator for survival. Mechanistically, MELK bound to and phosphorylated EZH2, and its methylation was induced by EZH2 in medulloblastoma, which could regulate the proliferation of cancer stemlike cells. In xenografts, loss of MELK or EZH2 attenuated medulloblastoma stem-like cell-derived tumor growth and promoted differentiation. These findings indicate that MELK-induced phosphorylation and EZH2-mediated methylation in MELK/EZH2 pathway are essential for medulloblastoma stem-like cell-derived tumor proliferation, thereby identifying a potential therapeutic strategy for these patients.Implications: This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness, thus representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma.Mol Cancer Res; 15(9); 1275-86. Ó2017 AACR.

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“…Moreover, HDAC and MEK1/2 inhibitors cooperate to reduce viability in MB cells and, as with HDACi, MAPK/ERK inhibition hinders neurosphere formation. The cell lines we used have been recently characterized to represent two distinct MB molecular subgroups: D283 cells display MYC amplification and are classified as Group 3/4 MB, whereas Daoy cells are TP53-mutated and represent SHH MB (Ivanov et al, 2016).…”

Section: We Have Previously Shown Responsiveness Of Human Mb Cells Anmentioning

confidence: 99%

HDAC and MAPK/ERK Inhibitors Cooperate to Reduce Viability and Stemness in Medulloblastoma

Jaeger

Ghisleni

Cardoso

et al. 2019

Preprint

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Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood.Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as a therapeutic tool to target this cell population. Here, we observed changes in the stemness phenotype induced by HDAC inhibition in MB. Analyses of MB tumor samples showed that the stemness markers BMI1 and CD133 are expressed in all molecular subgroups of MB. We then treated human MB cells with the HDAC inhibitor (HDACi) sodium butyrate (NaB). Increased acetylation mediated by NaB reduced cell viability and expression of BMI1 and CD133. Activation of extracellular-regulated kinase (ERK) signaling was also decreased after treatment with NaB.Enrichment analysis of genes associated with CD133 or BMI1 expression showed mitogenactivated protein kinase (MAPK)/ERK signaling and related pathways as the most enriched processes. We went on to use the mitogen-activated protein kinase kinase (MEK) inhibitor U0126 to explore the role of MAPK/ERK pathway. MEK inhibition reduced expression of the stemness markers, hindered MB neurosphere formation, and its antiproliferative effect was enhanced by combination with NaB. These results suggest that combining HDAC and MAPK/ERK inhibitors may be more effective in reducing MB proliferation than single-drug treatments, through modulation of the stemness phenotype of MB cells. 5 Keywords: Histone deacetylase Extracellular-regulated kinase Stemness Medulloblastoma Brain tumor 6

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In vitro models of medulloblastoma: Choosing the right tool for the job

Cited by 182 publications

References 167 publications

Establishment and characterization of an orthotopic patient-derived Group 3 medulloblastoma model for preclinical drug evaluation

Establishment and characterization of an orthotopic patient-derived Group 3 medulloblastoma model for preclinical drug evaluation

MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation

HDAC and MAPK/ERK Inhibitors Cooperate to Reduce Viability and Stemness in Medulloblastoma

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