The transcriptional network for mesenchymal transformation of brain tumours.
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/EBPbeta and STAT3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPbeta 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/EBPbeta 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.
Carro
Maria Stella
MS
Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA.
Lim
Wei Keat
WK
Alvarez
Mariano Javier
MJ
Bollo
Robert J
RJ
Zhao
Xudong
X
Snyder
Evan Y
EY
Sulman
Erik P
EP
Anne
Sandrine L
SL
Doetsch
Fiona
F
Colman
Howard
H
Lasorella
Anna
A
Aldape
Ken
K
Califano
Andrea
A
Iavarone
Antonio
A
D000818:Animals; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D065150:Cellular Reprogramming / Q000235:genetics; D019295:Computational Biology; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005910:Glioma / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D015203:Reproducibility of Results; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human