Article

An Animal Model of MYC-Driven Medulloblastoma

Tumor Development Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Cancer cell (Impact Factor: 23.52). 02/2012; 21(2):155-67. DOI: 10.1016/j.ccr.2011.12.021
Source: PubMed

ABSTRACT

Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC) usually have an extremely poor prognosis, but there are no animal models of this subtype of the disease. Here, we show that cerebellar stem cells expressing Myc and mutant Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells can give rise to MYC-driven MB and identify a novel model that can be used to test therapies for this devastating disease.

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Available from: Yoon-Jae Cho
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    • "Bcl-2 and Myc -Tp53 showed LCA cytoarchitecture and a high rate of metastatic dissemination to the spine. Other investigators have shown that Myc-expressing, Tp53-deficient mouse neural progenitor cells form LCA medulloblastomas when implanted orthotopically in immunocompromised hosts[9,10]. The gene expression profiles of the engrafted mouse tumors closely match those of human Group 3 medulloblastomas, showing increased expression of known Myc transcriptional targets and decreased expression of genes associated with neuronal differentiation. "
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    ABSTRACT: A highly aggressive subgroup of the pediatric brain tumor medulloblastoma is characterized by overexpression of the proto-oncogene c-Myc, which encodes a transcription factor that normally maintains neural progenitor cells in an undifferentiated, proliferating state during embryonic development. Myc-driven medulloblastomas typically show a large-cell anaplastic (LCA) histological pattern, in which tumor cells display large, round nuclei with prominent nucleoli. This subgroup of medulloblastoma is therapeutically challenging because it is associated with a high rate of metastatic dissemination, which is a powerful predictor of short patient survival times. Genetically engineered mouse models have revealed important insights into the pathogenesis of medulloblastoma and served as preclinical testing platforms for new therapies. Here we report a new mouse model of Myc-driven medulloblastoma, in which tumors arise in situ after retroviral transfer and expression of Myc in Nestin-expressing neural progenitor cells in the cerebella of newborn mice. Tumor induction required concomitant loss of Tp53 or overexpression of the antiapoptotic protein Bcl-2. Like Myc-driven medulloblastomas in humans, the tumors induced in mice by Myc + Bcl-2 and Myc − Tp53 showed LCA cytoarchitecture and a high rate of metastatic dissemination to the spine. The fact that Myc − Tp53 tumors arose only in Tp53 −/− mice, coupled with the inefficient germline transmission of the Tp53-null allele, made retroviral transfer of Myc + Bcl-2 a more practical method for generating LCA medulloblastomas. The high rate of spinal metastasis (87 % of brain tumor–bearing mice) will be an asset for testing new therapies that target the most lethal aspect of medulloblastoma.
    Full-text · Article · Oct 2015 · Journal of Neuro-Oncology
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    • "In addition, current MB research is intensely focusing on developing accurate mouse models of MYC-driven MB. To overcome MYC-induced apoptosis, two recently developed MYC-driven mouse MB models require loss of p53 [36,37]. Because JAG2 appeared to cooperate with MYC to protect MYC-overexpressing cells from apoptosis, JAG2 induction/up-regulation could be a useful strategy for the development of such high-MYC-expressing MB animal models. "
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    ABSTRACT: Medulloblastoma (MB), the most common pediatric malignant brain cancer, typically arises as pathological result of deregulated developmental pathways, including the NOTCH signaling cascade. Unlike the evidence supporting a role for NOTCH receptors in MB development, the pathological functions of NOTCH ligands remain largely unexplored. By examining the expression in large cohorts of MB primary tumors, and in established in vitro MB models, this research study demonstrates that MB cells bear abnormal levels of distinct NOTCH ligands. We explored the potential association between NOTCH ligands and the clinical outcome of MB patients, and investigated the rational of inhibiting NOTCH signaling by targeting specific ligands to ultimately provide therapeutic benefits in MB. The research revealed a significant over-expression of ligand JAG1 in the vast majority of MBs, and proved that JAG1 mediates pro-proliferative signals via activation of NOTCH2 receptor and induction of HES1 expression, thus representing an attractive therapeutic target. Furthermore, we could identify a clinically relevant association between ligand JAG2 and the oncogene MYC, specific for MYC-driven Group 3 MB cases. We describe for the first time a mechanistic link between the oncogene MYC and NOTCH pathway in MB, by identifying JAG2 as MYC target, and by showing that MB cells acquire induced expression of JAG2 through MYC-induced transcriptional activation. Finally, the positive correlation of MYC and JAG2 also with aggressive anaplastic tumors and highly metastatic MB stages suggested that high JAG2 expression may be useful as additional marker to identify aggressive MBs.
    Full-text · Article · Apr 2014
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    • "Group 3 tumors were also found to be significantly enriched for mutations that are predicted to activate TGF-β signaling (Northcott et al., 2012a). Two mouse models for MYC-amplified Group 3 tumors were recently developed, yielding an important tool for the study of these tumors (Kawauchi et al., 2012; Pei et al., 2012). "
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    ABSTRACT: Medulloblastoma, the most common malignant brain tumor in children, is a disease whose mechanisms are now beginning to be uncovered by high-throughput studies of somatic mutations, mRNA expression patterns, and epigenetic profiles of patient tumors. One emerging theme from studies that sequenced the tumor genomes of large cohorts of medulloblastoma patients is frequent mutation of RNA binding proteins. Proteins which bind multiple RNA targets can act as master regulators of gene expression at the post-transcriptional level to co-ordinate cellular processes and alter the phenotype of the cell. Identification of the target genes of RNA binding proteins may highlight essential pathways of medulloblastomagenesis that cannot be detected by study of transcriptomics alone.Furthermore, a subset of RNA binding proteins are attractive drug targets. For example, compounds that are under development as anti-viral targets due to their ability to inhibit RNA helicases could also be tested in novel approaches to medulloblastoma therapy by targeting key RNA binding proteins. In this review, we discuss a number of RNA binding proteins, including Musashi1 (MSI1), DEAD (Asp-Glu-Ala-Asp) box helicase 3 X-linked (DDX3X), DDX31, and cell division cycle and apoptosis regulator 1 (CCAR1), which play potentially critical roles in the growth and/or maintenance of medulloblastoma.
    Full-text · Article · Mar 2014 · Moleculer Cells
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