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


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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    • "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.
    04/2014; 2(1):39. DOI:10.1186/2051-5960-2-39
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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.
    Moleculer Cells 03/2014; 37(5). DOI:10.14348/molcells.2014.0008 · 2.09 Impact Factor
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    • "About 70% of patients carry a germ line p53 mutation.23 While medulloblastoma rarely occurs in p53−/− mice, homozygous loss of p53 accelerates the rate and frequency of occurrence of this tumor in PTCH+/− or Myc expressing mouse models.24 The role of germ line p53 mutation in the induction or prognosis of human medulloblastoma has been controversial over the years,23 but two recent studies have attempted to address this issue.25,26 "
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    ABSTRACT: Medulloblastoma is the commonest malignant brain tumor in children. Treatment with surgery, irradiation, and chemotherapy has improved outcomes in recent years, but patients are frequently left with devastating neurocognitive and other sequelae following such therapy. While the prognosis has traditionally been based on conventional histopathology and clinical staging (based on age, extent of resection, and presence or absence of metastasis), it has become apparent in recent years that the inherent biology of the tumor plays a significant part in predicting survival and sometimes supersedes clinical or pathologic risk factors. The advent of deep sequencing gene technology has provided invaluable clues to the molecular makeup of this tumor and allowed neuro-oncologists to understand that medulloblastoma is an amalgamation of several distinct disease entities with unique clinical associations and behavior. This review is a concise summary of the pathology, genetic syndromes, recent advances in molecular subgrouping, and the associated gene mutations and copy number variations in medulloblastoma. The association of molecular alterations with patient prognosis is also discussed, but it should be remembered that further validation is required in prospective clinical trials utilizing uniform treatment approaches.
    Pharmacogenomics and Personalized Medicine 02/2014; 7(1):43-51. DOI:10.2147/PGPM.S38698
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