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.
Glioblastoma is a nasty, aggressive form of cancer but no one has really known why or how to stop it growing, as a long line of therapies have proven largely ineffective.
This fascinating and important study identifies two genes, C/EBP and Stat3, which are active in about 60% of glioblastoma patients. They appear to work in tandem to turn on many other genes that make brain cells cancerous.
Patients in the study whose tumours showed evidence of both genes being active died within 140 weeks of diagnosis. In comparison, half of patients without activity from these genes were alive after that time, suggesting the two genes may have a role to play as 'master controls' in the disease, driving cells in the brain to become glioblastoma cells.
Of course, future focus will shift to developing effective targeted therapy against the genes to determine whether inactivating them will have any effect on the cancer.
Time will tell. Watch this space!
Carro, M., Lim, W., Alvarez, M., Bollo, R., Zhao, X., Snyder, E., Sulman, E., Anne, S., Doetsch, F., Colman, H., Lasorella, A., Aldape, K., Califano, A., & Iavarone, A. (2009). The transcriptional network for mesenchymal transformation of brain tumours Nature DOI: 10.1038/nature08712