Medulloblastoma is the most common malignant brain tumor in children. Its rapid growth and tendency to spread through the nervous system make it extremely difficult to treat, and more than 40% of the children who develop the disease die from it. Improved treatment of medulloblastoma is likely to come from a deeper understanding of the signals that control normal cerebellar development, and an appreciation of how these signals are dysregulated in tumors. To identify such signals, we have studied an animal model of medulloblastoma - the patched mutant mouse - and identified genes whose expression is altered in tumor cells compared to granule cell precursors (GCPs), the cells from which the tumor is believed to arise. Among the genes whose expression decreased most significantly was Unc5c, which encodes a receptor for the netrin family of signaling molecules. Unc5c was originally described as a regulator of cell migration, but has recently been shown to play an important role in apoptosis as well. Moreover, Unc5c is deleted or mutated in a variety of cancers, and has therefore been suggested to function as a tumor suppressor. We hypothesize that Unc5c controls migration and survival of GCPs during normal cerebellar development, and that its loss contributes to the abnormal migration and increased survival observed in medulloblastoma. If this hypothesis is correct, it will have important implications for our understanding of medulloblastoma, and open up new avenues for treatment of the disease. To test our hypothesis, we propose to: 1) Determine whether Unc5c regulates inward migration of granule cell precursors and tumor cells 2) Test whether Unc5c regulates survival of granule cell precursors and tumor cells 3) Determine whether loss of Unc5c is required for medulloblastoma formation Relevance to Public Health: One of the greatest challenges in medulloblastoma treatment is the ability of tumor cells to migrate into regions where they would not normally go, and to survive once they get there. Our observation of altered Unc5c expression in medulloblastoma is significant because it can contribute to both of these behaviors. By elucidating the role of Unc5c in migration and survival, our studies will shed light on the molecular mechanisms that underlie the aggressive growth and dissemination of medulloblastoma. This, in turn, will pave the way for developing new treatments that can be used to fight this devastating disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS052323-01A1
Application #
7150352
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2006-06-01
Project End
2011-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
1
Fiscal Year
2006
Total Cost
$337,617
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Li, Peng; Du, Fang; Yuelling, Larra W et al. (2013) A population of Nestin-expressing progenitors in the cerebellum exhibits increased tumorigenicity. Nat Neurosci 16:1737-44
Markant, Shirley L; Esparza, Lourdes Adriana; Sun, Jesse et al. (2013) Targeting sonic hedgehog-associated medulloblastoma through inhibition of Aurora and Polo-like kinases. Cancer Res 73:6310-22
Sengupta, Rajarshi; Dubuc, Adrian; Ward, Stacey et al. (2012) CXCR4 activation defines a new subgroup of Sonic hedgehog-driven medulloblastoma. Cancer Res 72:122-32
Read, Tracy-Ann; Fogarty, Marie P; Markant, Shirley L et al. (2009) Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell 15:135-47
Yang, Zeng-Jie; Ellis, Tammy; Markant, Shirley L et al. (2008) Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14:135-45
Emmenegger, Brian A; Wechsler-Reya, Robert J (2008) Stem cells and the origin and propagation of brain tumors. J Child Neurol 23:1172-8
Tallal, P; Stark, R E; Mellits, E D (1985) Identification of language-impaired children on the basis of rapid perception and production skills. Brain Lang 25:314-22