Document Detail

Transposon mutagenesis identifies genes that transform neural stem cells into glioma-initiating cells.
MedLine Citation:
PMID:  23045694     Owner:  NLM     Status:  MEDLINE    
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.
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
Related Documents :
19859084 - Association of sumo1 and ubc9 genotypes with tumor response in non-small-cell lung canc...
23160424 - Emerging operative strategies in neurosurgical oncology.
9665144 - Distinguishing second primary tumors from lung metastases in patients with head and nec...
3607754 - Thrombospondin, a potentiator of tumor cell metastasis.
19525924 - Pax2 expression in low malignant potential ovarian tumors and low-grade ovarian serous ...
12702584 - Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamo...
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
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Brain Neoplasms / pathology*
Cell Transformation, Neoplastic
DNA Transposable Elements*
Glioblastoma / pathology*
Neural Stem Cells / cytology*
Grant Support
13031//Cancer Research UK
Reg. No./Substance:
0/DNA Transposable Elements

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

Previous Document:  Natriuretic peptides block synaptic transmission by activating phosphodiesterase 2A and reducing pre...
Next Document:  Dendritic cells sequester antigenic epitopes for prolonged periods in the absence of antigen-encodin...