Document Detail


Transposon mutagenesis identifies genes that transform neural stem cells into glioma-initiating cells.
MedLine Citation:
PMID:  23045694     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Neural stem cells (NSCs) are considered to be the cell of origin of glioblastoma multiforme (GBM). However, the genetic alterations that transform NSCs into glioma-initiating cells remain elusive. Using a unique transposon mutagenesis strategy that mutagenizes NSCs in culture, followed by additional rounds of mutagenesis to generate tumors in vivo, we have identified genes and signaling pathways that can transform NSCs into glioma-initiating cells. Mobilization of Sleeping Beauty transposons in NSCs induced the immortalization of astroglial-like cells, which were then able to generate tumors with characteristics of the mesenchymal subtype of GBM on transplantation, consistent with a potential astroglial origin for mesenchymal GBM. Sequence analysis of transposon insertion sites from tumors and immortalized cells identified more than 200 frequently mutated genes, including human GBM-associated genes, such as Met and Nf1, and made it possible to discriminate between genes that function during astroglial immortalization vs. later stages of tumor development. We also functionally validated five GBM candidate genes using a previously undescribed high-throughput method. Finally, we show that even clonally related tumors derived from the same immortalized line have acquired distinct combinations of genetic alterations during tumor development, suggesting that tumor formation in this model system involves competition among genetically variant cells, which is similar to the Darwinian evolutionary processes now thought to generate many human cancers. This mutagenesis strategy is faster and simpler than conventional transposon screens and can potentially be applied to any tissue stem/progenitor cells that can be grown and differentiated in vitro.
Authors:
Hideto Koso; Haruna Takeda; Christopher Chin Kuan Yew; Jerrold M Ward; Naoki Nariai; Kazuko Ueno; Masao Nagasaki; Sumiko Watanabe; Alistair G Rust; David J Adams; Neal G Copeland; Nancy A Jenkins
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Publication Detail:
Type:  Journal Article     Date:  2012-10-08
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-11-01     Completed Date:  2013-01-08     Revised Date:  2014-08-12    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E2998-3007     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE3689;  GSE36897
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MeSH Terms
Descriptor/Qualifier:
Animals
Brain Neoplasms / pathology*
Cell Transformation, Neoplastic
DNA Transposable Elements*
Glioblastoma / pathology*
Humans
Mice
Mutagenesis*
Neural Stem Cells / cytology*
Grant Support
ID/Acronym/Agency:
13031//Cancer Research UK
Chemical
Reg. No./Substance:
0/DNA Transposable Elements
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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