Glioma is the most common type of malignant brain tumor. Despite widespread advances in cancer medicine, this devastating disease remains incurable. Recently, it was reported that gliomas contain a population of tumor stem cells that can form self renewable tumor spheres in culture and re- initiate gliomas after transplantation into immuno-suppressed mice. Targeting these tumor stem cells is an exciting prospect towards a glioma cure. However, critical information required to develop such therapeutic strategies, including the developmental origin of the glioma stem cells, remains unknown. To address the tumor cell of origin problem, it requires the use of glioma animal models that allow the analysis of early-stage pre-malignant tumor cells. Unfortunately, current mouse models cannot provide adequate in vivo resolution for such studies. Our laboratory has developed a new mouse glioma model based on a novel genetic mosaic system termed MADM (Mosaic Analysis with Double Markers, Zong et al Cell 2005). Using MADM, we can generate rare, green fluorescent protein (GFP)-labeled neural stem cells (NSCs) that are double null for two key tumor suppressor genes, p53 and Neurofibromatosis Type 1 (NF1), within an otherwise normal mouse. This approach allows us to analyze the entire course of gliomagenesis with single-cell resolution in vivo. Our preliminary findings show that, although the mutations are generated specifically in NSCs, resulting glioma cells manifest many cellular features of oligodendrocyte precursors (OPCs). Prior to malignancy, OPCs are the only cell lineage that drastically over-expands in the MADM mice. In the glioma tumor mass, OPCs are also the predominant cell type that maintains active cell divisions. When we purify these OPC-like glioma cells they manifest salient glioma stem cell features, including forming renewable tumor spheres, differentiating into multiple cell lineages, and reinitiating gliomas after being transplanted into immuno-suppressed mice. Based on these preliminary results, we will test the following hypothesis: 1) OPCs are the key cell type that initiates and renews gliomagenesis;2) mutant OPCs can de-differentiate to acquire stem cell properties;and 3) targeting OPCs or their stem-cell characteristics will be effective treatment strategies for gliomas. Our proposed studies will lead to valuable basic understanding of the developmental process of gliomas. The identification of tumor-initiating cells should provide a basis for designing rationale treatment strategies for the cure. Conceptually, our proposed work explores the uncharted territory of tumor initiation, and provides critical groundwork for the refinement of mouse models for mechanistic understanding of human cancers.

Public Health Relevance

Studies proposed in this grant aim at the identification of the origin of cancer stem cells for glioma, a currently incurable disease. A thorough understanding of these cells should enable the design of rationale therapeutic strategies by targeting specific cells or genes to treat gliomas. As a consequence, the enhanced specificity should lead to more effective and less toxic drugs, which could eventually provide a cure for gliomas.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Genetics Study Section (CG)
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Lin, Alison J
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University of Virginia
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Gonzalez, Phillippe P; Kim, Jungeun; Galvao, Rui Pedro et al. (2018) p53 and NF 1 loss plays distinct but complementary roles in glioma initiation and progression. Glia 66:999-1015
Ledur, Pítia Flores; Onzi, Giovana Ravizzoni; Zong, Hui et al. (2017) Culture conditions defining glioblastoma cells behavior: what is the impact for novel discoveries? Oncotarget 8:69185-69197
Ledur, Pítia F; Liu, Chong; He, Hua et al. (2016) Culture conditions tailored to the cell of origin are critical for maintaining native properties and tumorigenicity of glioma cells. Neuro Oncol 18:1413-24
Zong, Hui; Parada, Luis F; Baker, Suzanne J (2015) Cell of origin for malignant gliomas and its implication in therapeutic development. Cold Spring Harb Perspect Biol 7:
Zong, Hui (2014) Generation and applications of MADM-based mouse genetic mosaic system. Methods Mol Biol 1194:187-201
Galvao, Rui Pedro; Kasina, Anita; McNeill, Robert S et al. (2014) Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process. Proc Natl Acad Sci U S A 111:E4214-23
Henner, Astra; Ventura, P Britten; Jiang, Ying et al. (2013) MADM-ML, a mouse genetic mosaic system with increased clonal efficiency. PLoS One 8:e77672
Galvao, Rui Pedro; Zong, Hui (2013) Inflammation and Gliomagenesis: Bi-Directional Communication at Early and Late Stages of Tumor Progression. Curr Pathobiol Rep 1:19-28
Papagiannakopoulos, T; Friedmann-Morvinski, D; Neveu, P et al. (2012) Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene 31:1884-95
Liu, Chong; Zong, Hui (2012) Developmental origins of brain tumors. Curr Opin Neurobiol 22:844-9

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