The transcriptional network for mesenchymal transformation of brain tumours

Maria Stella Carro, Wei Keat Lim, Mariano Javier Alvarez, Robert J. Bollo, Xudong Zhao, Evan Y. Snyder, Erik P. Sulman, Sandrine L. Anne, Fiona Doetsch, Howard Colman, Anna Lasorella, Ken Aldape, Andrea Califano () and Antonio Iavarone ()
Additional contact information
Maria Stella Carro: Institute for Cancer Genetics,
Wei Keat Lim: Department of Biomedical Informatics,
Mariano Javier Alvarez: Center for Computational Biology and Bioinformatics,
Robert J. Bollo: New York University School of Medicine & NYU Langone Medical Center, New York, New York 10016, USA
Xudong Zhao: Institute for Cancer Genetics,
Evan Y. Snyder: Burnham Institute for Medical Research, La Jolla, California 92037, USA
Erik P. Sulman: Division of Radiation Oncology,
Sandrine L. Anne: Institute for Cancer Genetics,
Fiona Doetsch: Department of Pathology,
Howard Colman: Department of Neuro-Oncology,
Anna Lasorella: Institute for Cancer Genetics,
Ken Aldape: M.D. Anderson Cancer Center, Houston, Texas 77030, USA
Andrea Califano: Institute for Cancer Genetics,
Antonio Iavarone: Institute for Cancer Genetics,

Nature, 2010, vol. 463, issue 7279, 318-325

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature08712

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