The transcriptional network for mesenchymal transformation of brain tumours

• Published in: Nature (London) 2010-01, Vol.463 (7279), p.318-325
• Main Authors: Lasorella, Anna, Lim, Wei Keat, Carro, Maria Stella, Anne, Sandrine L, Alvarez, Mariano Javier, Doetsch, Fiona, Aldape, Ken, Iavarone, Antonio, Colman, Howard, Zhao, Xudong, Snyder, Evan Y, Sulman, Erik P, Califano, Andrea, Bollo, Robert J
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain; Brain cancer; Brain Neoplasms - diagnosis; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain tumors; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Differentiation - genetics; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cellular Reprogramming - genetics; Computational Biology; Gene expression; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genetic aspects; Genetic transcription; Genotype & phenotype; Glioma - diagnosis; Glioma - genetics; Glioma - pathology; Gliomas; Humanities and Social Sciences; Humans; Medical sciences; Mesenchymal Stromal Cells - metabolism; Mesenchymal Stromal Cells - pathology; Mesoderm - metabolism; Mesoderm - pathology; Mice; Mice, Inbred NOD; Mice, SCID; multidisciplinary; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neurology; Neurons - metabolism; Neurons - pathology; Physiological aspects; Prognosis; Proteins; Regression analysis; Reproducibility of Results; Reverse engineering; Risk factors; Science; Science (multidisciplinary); STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Stem cells; Transcription factors; Transcription, Genetic; Tumors of the nervous system. Phacomatoses
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08712

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. Mastering tumorigenicity Some highly aggressive human glioblastomas express genes characteristic of a mesenchymal phenotype, and this signature is known to be associated with poor prognosis. Using a bio-informatics approach, the transcription factors STAT3 and C/EBPβ have been identified as master regulators of this mesenchymal phenotype. They cooperate to promote tumorigenesis and invasion, and elimination of both factors leads to a collapse in mesenchymal gene expression and reduces tumour aggressiveness. This systems biology method of identifying master regulators that choreograph malignancy could help to predict clinical outcomes and could open the door to new therapeutic strategies. 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. Reverse-engineering and an unbiased interrogation of a glioma-specific regulatory network now reveal the transcription factors that activate expression of mesenchymal genes in malignant glioma.