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- Title
The transcriptional network for mesenchymal transformation of brain tumours.
- Authors
Carro, Maria Stella; Wei Keat Lim; Alvarez, Mariano Javier; Bollo, Robert J.; Xudong Zhao; Snyder, Evan Y.; Sulman, Erik P.; Anne, Sandrine L.; Doetsch, Fiona; Colman, Howard; Lasorella, Anna; Aldape, Ken; Califano, Andrea; Iavarone, Antonio
- 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.
- Subjects
SYSTEMS biology; PHENOTYPES; BRAIN tumors; GLIOBLASTOMA multiforme; CENTRAL nervous system; CANCER cells; GENE expression; TRANSCRIPTION factors; NERVE tissue
- Publication
Nature, 2010, Vol 463, Issue 7279, p318
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature08712