Medulloblastoma, a common form of primitive neuroectodermal tumor (PNET), is among the most malignant of the pediatric brain tumors with an average 5-year survival rate of only 50%. Medulloblastoma is believed to arise from the undifferentiated external granule layer (EGL) cells in the cerebellum but the mechanism remains unknown. Our preliminary results suggested a novel mechanism for the development of medulloblastoma. We found that medulloblastoma cell lines overexpress a transcriptional repressor, RE1-Silencing Transcription Factor (REST)/Neuron Restrictive Silencer Factor (NRSF), that countering the actions of REST/NRSF inhibits the cells' tumorigenic potential in nude mice, and that 50% of human medulloblastoma tumor specimens overexpress REST/NRSF. Our more recent experiments indicated that when neuronal stem cells (NSCs), which do not normally express REST/NRSF, are engineered to overexpress REST/NRSF, they form intracranial PNET-like tumors in nude mice. Thus, our working hypothesis is that overexpression of REST/NRSF in NSCs cause medulloblastoma in vivo. In this grant, the following 3 Specific Aims are proposed. First, our hypothesis will be tested by, using the reporter gene-tagged NSC line, C17.2, which resemble EGL cells and can be traced after intracranial implantation. REST/NRSF and another reporter gene (GFP) will be stably and inducibly coexpressed in C17.2 cells and their intracranial tumorigenic potential will be examined in newborn, young, and adult mice. The role of the two repressor domains of REST/NRSF in this process will also be determined. Because of the GFP expression, this orthotopic mouse model will also be a noninvasive system for studying tumor properties by optical imaging. Second, transgenic mice expressing inducible levels of REST/NRSF will be constructed to determine whether the hypothesis is correct under physiological conditions. Third, as REST/NRSF controls transcription by modulating chromatin, a recently developed novel chromatin reconstitution system will be used to identify these interactions and examine their roles in medulloblastoma formation. Thus, by combining developmental biology, transcription biology, and cancer biology, the proposed studies will yield critical information towards our long-term goal of studying the genesis of medulloblastoma and produce mechanism-based animal models that can be used to identify new, physiologically relevant targets for therapy and to test both existing and new drugs for medulloblastoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097124-03
Application #
6800098
Study Section
Special Emphasis Panel (ZRG1-PTHC (01))
Program Officer
Mietz, Judy
Project Start
2002-09-17
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$268,780
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Lu, Li; Marisetty, Anantha; Liu, Bin et al. (2018) REST overexpression in mice causes deficits in spontaneous locomotion. Sci Rep 8:12083
Marisetty, Anantha L; Singh, Sanjay K; Nguyen, Tran N et al. (2017) REST represses miR-124 and miR-203 to regulate distinct oncogenic properties of glioblastoma stem cells. Neuro Oncol 19:514-523
Singh, Sanjay K; Marisetty, Anantha; Sathyan, Pratheesh et al. (2015) REST-miR-21-SOX2 axis maintains pluripotency in E14Tg2a.4 embryonic stem cells. Stem Cell Res 15:305-11
Sathyan, Pratheesh; Zinn, Pascal O; Marisetty, Anantha L et al. (2015) Mir-21-Sox2 Axis Delineates Glioblastoma Subtypes with Prognostic Impact. J Neurosci 35:15097-112
Kamal, Mohamed M; Sathyan, Pratheesh; Singh, Sanjay K et al. (2012) REST regulates oncogenic properties of glioblastoma stem cells. Stem Cells 30:405-14
Singh, Sanjay K; Veo, Bethany L; Kagalwala, Mohamedi N et al. (2012) Dynamic status of REST in the mouse ESC pluripotency network. PLoS One 7:e43659
Gopalakrishnan, Vidya; Bie, Bihua; Sinnappah-Kang, Neeta D et al. (2010) Myoblast-derived neuronal cells form glutamatergic neurons in the mouse cerebellum. Stem Cells 28:1839-47
Singh, Sanjay K; Kagalwala, Mohamedi N; Parker-Thornburg, Jan et al. (2008) REST maintains self-renewal and pluripotency of embryonic stem cells. Nature 453:223-7
Kagalwala, M N; Singh, S K; Majumder, S (2008) Stemness is only a state of the cell. Cold Spring Harb Symp Quant Biol 73:227-34
Majumder, Sadhan (2006) REST in good times and bad: roles in tumor suppressor and oncogenic activities. Cell Cycle 5:1929-35

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