The transcriptional network for mesenchymal transformation of brain tumours
Top Cited Papers
Open Access
- 23 December 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 463 (7279), 318-325
- https://doi.org/10.1038/nature08712
Abstract
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/EBPβ and STAT3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ 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/EBPβ 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.Keywords
This publication has 53 references indexed in Scilit:
- The N-Myc-DLL3 Cascade Is Suppressed by the Ubiquitin Ligase Huwe1 to Inhibit Proliferation and Promote Neurogenesis in the Developing BrainDevelopmental Cell, 2009
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoproteinNature, 2008
- Variations in DNA elucidate molecular networks that cause diseaseNature, 2008
- A systems biology approach to prediction of oncogenes and molecular perturbation targets in B‐cell lymphomasMolecular Systems Biology, 2008
- NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growthProceedings of the National Academy of Sciences of the United States of America, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Integrative analysis of the cancer transcriptomeNature Genetics, 2005
- Reverse engineering of regulatory networks in human B cellsNature Genetics, 2005
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001