Medulloblastoma (MB) is the most common malignant brain tumor in children. MB is thought to arise from progenitor cells in the developing cerebellum that fail to exit the cell division cycle properly, thus providing fertile ground for tumor formation. Many genetic anomalies have been identified in human MB, but only a few have been revealed to be causative. We have genetically engineered two different MB-prone mouse strains that lack the cyclin-D-dependent kinase inhibitor, p18lnk4c, a cell cycle regulatory and tumor suppressor protein whose expression was also revealed to be reduced or absent in human MBs.
In Specific Aim 1, we propose to document the frequency of inactivation of INK4C/CDKN2C in human MBs and to correlate its loss-of-function with other genetic mutations, gene copy number alterations, and gene expression profiles that define different human MB subsets. We will also explore the combined roles of the C-MYC oncoprotein and p53 tumor suppressor in generating a mouse model of large cell anaplastic MBs, the most aggressive and treatment-resistant form of the disease. Many mouse MBs are characterized by mutations affecting a signaling pathway dominated by the mitogen, Sonic Hedgehog (Shh);genetic alterations affecting the Shh signaling pathway have similarly been documented in a subset of human MBs. Our work has established a role for the bone morphogenic proteins (BMPs) in countering Shh signaling, thereby inhibiting proliferation of mouse MBs, and fostering their neuronal differentiation. Not only do BMPs strongly antagonize MB formation in our mouse models, but downregulation of many BMP-responsive genes is a hallmark of Shh-driven human tumors.
In Specific Aim 2, we will study Mathl, a key transcription factor regulated by BMP signaling in an'effort to discern how the activity of this protein is governed, what genes it regulates, and why its role is seemingly essential for MB development. Finally, it is now widely appreciated that small regulatory RNA species (micro-RNAs) globally regulate gene expression and thereby contribute to many forms of cancer.
In Specific Aim 3, we propose methods to characterize in detail the micro-RNAs that contribute to MB formation and tumor maintenance in both mice and humans.

Public Health Relevance

Although many MB patients are cured by combined surgery, radiotherapy and chemotherapy, these aggressive treatments often lead to devastating defects in neurocognitive functions. An improved molecular understanding of those gene products that are instrumental in causing MB should lead to the identification of new druggable targets and to advances in the treatment of this catastrophic tumor of childhood.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA096832-10
Application #
8459551
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$253,755
Indirect Cost
$85,370
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Eden, C J; Ju, B; Murugesan, M et al. (2015) Orthotopic models of pediatric brain tumors in zebrafish. Oncogene 34:1736-42
Parker, Matthew; Mohankumar, Kumarasamypet M; Punchihewa, Chandanamali et al. (2014) C11orf95-RELA fusions drive oncogenic NF-?B signalling in ependymoma. Nature 506:451-5
Huether, Robert; Dong, Li; Chen, Xiang et al. (2014) The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat Commun 5:3630
Wu, Gang; Diaz, Alexander K; Paugh, Barbara S et al. (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444-50
Katyal, Sachin; Lee, Youngsoo; Nitiss, Karin C et al. (2014) Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes. Nat Neurosci 17:813-21
Diaz, Alexander K; Baker, Suzanne J (2014) The genetic signatures of pediatric high-grade glioma: no longer a one-act play. Semin Radiat Oncol 24:240-7
Northcott, Paul A; Lee, Catherine; Zichner, Thomas et al. (2014) Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511:428-34
Lee, Youngsoo; Brown, Eric J; Chang, Sandy et al. (2014) Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss. J Neurosci 34:7836-44
Morfouace, Marie; Shelat, Anang; Jacus, Megan et al. (2014) Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma. Cancer Cell 25:516-29
Jones, Chris; Baker, Suzanne J (2014) Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nat Rev Cancer 14:

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