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 #
5P01CA096832-09
Application #
8375494
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$306,287
Indirect Cost
$102,462
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Dumitrache, Lavinia C; McKinnon, Peter J (2017) Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease. Mech Ageing Dev 161:121-129
Hoch, Nicolas C; Hanzlikova, Hana; Rulten, Stuart L et al. (2017) XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541:87-91
Vo, BaoHan T; Li, Chunliang; Morgan, Marc A et al. (2017) Inactivation of Ezh2 Upregulates Gfi1 and Drives Aggressive Myc-Driven Group 3 Medulloblastoma. Cell Rep 18:2907-2917
Wei, Lei; Murphy, Brian L; Wu, Gang et al. (2017) Exome sequencing analysis of murine medulloblastoma models identifies WDR11 as a potential tumor suppressor in Group 3 tumors. Oncotarget 8:64685-64697
Illuzzi, Jennifer L; McNeill, Daniel R; Bastian, Paul et al. (2017) Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes. Environ Mol Mutagen 58:84-98
Genthe, Jamie R; Min, Jaeki; Farmer, Dana M et al. (2017) Ventromorphins: A New Class of Small Molecule Activators of the Canonical BMP Signaling Pathway. ACS Chem Biol 12:2436-2447
Pajtler, Kristian W; Mack, Stephen C; Ramaswamy, Vijay et al. (2017) The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 133:5-12
Fukuda, Yu; Wang, Yao; Lian, Shangli et al. (2017) Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesis. JCI Insight 2:
Nakanishi, Takeo; Ohno, Yasuhiro; Aotani, Rika et al. (2017) A novel role for OATP2A1/SLCO2A1 in a murine model of colon cancer. Sci Rep 7:16567
Enriquez-Rios, Vanessa; Dumitrache, Lavinia C; Downing, Susanna M et al. (2017) DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neurogenesis. J Neurosci 37:893-905

Showing the most recent 10 out of 186 publications