Publication Date:
2009-12-25
Description:
The inference of transcriptional networks that regulate transitions into physiological or pathological cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumour aggressiveness in human malignant glioma, but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here we show that reverse-engineering and an unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPbeta and STAT3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPbeta and STAT3 reprograms neural stem cells along the aberrant mesenchymal lineage, whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumour aggressiveness. In human glioma, expression of C/EBPbeta and STAT3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results show that the activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011561/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011561/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carro, Maria Stella -- Lim, Wei Keat -- Alvarez, Mariano Javier -- Bollo, Robert J -- Zhao, Xudong -- Snyder, Evan Y -- Sulman, Erik P -- Anne, Sandrine L -- Doetsch, Fiona -- Colman, Howard -- Lasorella, Anna -- Aldape, Ken -- Califano, Andrea -- Iavarone, Antonio -- 1RC2CA148308-01/CA/NCI NIH HHS/ -- P20 GM075059/GM/NIGMS NIH HHS/ -- P20GM075059/GM/NIGMS NIH HHS/ -- R01 CA085628/CA/NCI NIH HHS/ -- R01 CA101644/CA/NCI NIH HHS/ -- R01 CA109755/CA/NCI NIH HHS/ -- R01 CA127643/CA/NCI NIH HHS/ -- R01 NS061776/NS/NINDS NIH HHS/ -- R01 NS061776-01A2/NS/NINDS NIH HHS/ -- R01 NS061776-02/NS/NINDS NIH HHS/ -- R01CA085628/CA/NCI NIH HHS/ -- R01CA101644/CA/NCI NIH HHS/ -- R01CA109755/CA/NCI NIH HHS/ -- R01NS061776/NS/NINDS NIH HHS/ -- RC2 CA148308/CA/NCI NIH HHS/ -- U01 CA168426/CA/NCI NIH HHS/ -- U54 CA121852/CA/NCI NIH HHS/ -- U54CA121852/CA/NCI NIH HHS/ -- England -- Nature. 2010 Jan 21;463(7279):318-25. doi: 10.1038/nature08712. Epub 2009 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20032975" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Brain Neoplasms/diagnosis/*genetics/*pathology
;
CCAAT-Enhancer-Binding Protein-beta/genetics/metabolism
;
Cell Differentiation/genetics
;
Cell Line, Tumor
;
Cell Transformation, Neoplastic/genetics/metabolism/pathology
;
Cellular Reprogramming/genetics
;
Computational Biology
;
*Gene Expression Regulation, Neoplastic
;
*Gene Regulatory Networks
;
Glioma/diagnosis/genetics/pathology
;
Humans
;
Mesenchymal Stromal Cells/metabolism/pathology
;
Mesoderm/*metabolism/*pathology
;
Mice
;
Mice, Inbred NOD
;
Mice, SCID
;
Neoplasm Invasiveness/genetics/pathology
;
Neurons/metabolism/pathology
;
Prognosis
;
Reproducibility of Results
;
STAT3 Transcription Factor/genetics/metabolism
;
*Transcription, Genetic
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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