PMID- 20032975
OWN - NLM
STAT- MEDLINE
DCOM- 20100303
LR  - 20220310
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 463
IP  - 7279
DP  - 2010 Jan 21
TI  - The transcriptional network for mesenchymal transformation of brain tumours.
PG  - 318-25
LID - 10.1038/nature08712 [doi]
AB  - 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.
FAU - Carro, Maria Stella
AU  - Carro MS
AD  - Institute for Cancer Genetics, Columbia University Medical Center, New York, New 
      York 10032, USA.
FAU - Lim, Wei Keat
AU  - Lim WK
FAU - Alvarez, Mariano Javier
AU  - Alvarez MJ
FAU - Bollo, Robert J
AU  - Bollo RJ
FAU - Zhao, Xudong
AU  - Zhao X
FAU - Snyder, Evan Y
AU  - Snyder EY
FAU - Sulman, Erik P
AU  - Sulman EP
FAU - Anne, Sandrine L
AU  - Anne SL
FAU - Doetsch, Fiona
AU  - Doetsch F
FAU - Colman, Howard
AU  - Colman H
FAU - Lasorella, Anna
AU  - Lasorella A
FAU - Aldape, Ken
AU  - Aldape K
FAU - Califano, Andrea
AU  - Califano A
FAU - Iavarone, Antonio
AU  - Iavarone A
LA  - eng
SI  - GEO/GSE19113
SI  - GEO/GSE19114
GR  - R01 CA127643/CA/NCI NIH HHS/United States
GR  - 1RC2CA148308-01/CA/NCI NIH HHS/United States
GR  - R01 CA190891/CA/NCI NIH HHS/United States
GR  - R01 CA101644/CA/NCI NIH HHS/United States
GR  - U54 CA121852/CA/NCI NIH HHS/United States
GR  - R01 AI066116/AI/NIAID NIH HHS/United States
GR  - R01CA085628/CA/NCI NIH HHS/United States
GR  - R01 NS061776/NS/NINDS NIH HHS/United States
GR  - R01NS061776/NS/NINDS NIH HHS/United States
GR  - R01 NS061776-02/NS/NINDS NIH HHS/United States
GR  - RC2 CA148308/CA/NCI NIH HHS/United States
GR  - R01 CA085628/CA/NCI NIH HHS/United States
GR  - R01 NS061776-01A2/NS/NINDS NIH HHS/United States
GR  - U54CA121852/CA/NCI NIH HHS/United States
GR  - R01CA101644/CA/NCI NIH HHS/United States
GR  - U01 CA168426/CA/NCI NIH HHS/United States
GR  - P20 GM075059/GM/NIGMS NIH HHS/United States
GR  - R01CA109755/CA/NCI NIH HHS/United States
GR  - R01 CA109755/CA/NCI NIH HHS/United States
GR  - P20GM075059/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091223
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (CCAAT-Enhancer-Binding Protein-beta)
RN  - 0 (CEBPB protein, human)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
SB  - IM
MH  - Animals
MH  - Brain Neoplasms/diagnosis/*genetics/*pathology
MH  - CCAAT-Enhancer-Binding Protein-beta/genetics/metabolism
MH  - Cell Differentiation/genetics
MH  - Cell Line, Tumor
MH  - Cell Transformation, Neoplastic/genetics/metabolism/pathology
MH  - Cellular Reprogramming/genetics
MH  - Computational Biology
MH  - *Gene Expression Regulation, Neoplastic
MH  - *Gene Regulatory Networks
MH  - Glioma/diagnosis/genetics/pathology
MH  - Humans
MH  - Mesenchymal Stem Cells/metabolism/pathology
MH  - Mesoderm/*metabolism/*pathology
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Neoplasm Invasiveness/genetics/pathology
MH  - Neurons/metabolism/pathology
MH  - Prognosis
MH  - Reproducibility of Results
MH  - STAT3 Transcription Factor/genetics/metabolism
MH  - *Transcription, Genetic
PMC - PMC4011561
MID - NIHMS165691
EDAT- 2009/12/25 06:00
MHDA- 2010/03/04 06:00
PMCR- 2014/05/06
CRDT- 2009/12/25 06:00
PHST- 2009/09/02 00:00 [received]
PHST- 2009/11/30 00:00 [accepted]
PHST- 2009/12/25 06:00 [entrez]
PHST- 2009/12/25 06:00 [pubmed]
PHST- 2010/03/04 06:00 [medline]
PHST- 2014/05/06 00:00 [pmc-release]
AID - nature08712 [pii]
AID - 10.1038/nature08712 [doi]
PST - ppublish
SO  - Nature. 2010 Jan 21;463(7279):318-25. doi: 10.1038/nature08712. Epub 2009 Dec 23.