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The transcriptional network for mesenchymal transformation of brain tumours
Maria Stella Carro1,13,14, Wei Keat Lim2,3,13,14, Mariano Javier Alvarez3,4,13, Robert J. Bollo8, Xudong Zhao1, Evan Y. Snyder9, Erik P. Sulman10, Sandrine L. Anne1,14, Fiona Doetsch5, Howard Colman11, Anna Lasorella1,5,6, Ken Aldape12, Andrea Califano1,2,3,4 & Antonio Iavarone1,5,7
1 Institute for Cancer Genetics,
2 Department of Biomedical Informatics,
3 Center for Computational Biology and Bioinformatics,
4 Joint Centers for Systems Biology,
5 Department of Pathology,
6 Department of Pediatrics,
7 Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA
8 Department of Neurosurgery, New York University School of Medicine & NYU Langone Medical Center, New York, New York 10016, USA
9 Burnham Institute for Medical Research, La Jolla, California 92037, USA
10 Division of Radiation Oncology,
11 Department of Neuro-Oncology,
12 Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA
13 These authors contributed equally to this work.
14 Present addresses: Department of General Neurosurgery, Neurocenter and Comprehensive Cancer Research Center, University of Freiburg, Breisacher Str. 64, D-79106 Freiburg, Germany (M.S.C.); Therasis, Inc., 462 First Avenue, Suite 908, New York, New York 10016, USA (W.K.L.); Rockefeller University, RRB 750, 1230 York Avenue, New York, New York 10065, USA (S.L.A.).
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.
