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| Status |
Public on Feb 12, 2010 |
| Title |
A transcriptional module initiates and maintains mesenchymal transformation in brain tumors [human data] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Using a novel combination of cellular-network reverse-engineering algorithms and experimental validation assays, we identified a transcriptional module, including six transcription factors that synergistically regulates the mesenchymal signature of malignant glioma. This is a poorly understood molecular phenotype, never observed in normal neural tissue. It represents the hallmark of tumor aggressiveness in high-grade glioma, and its upstream regulation is so far unknown. Overall, the newly discovered transcriptional module regulates >74% of the signature genes, while two of its transcription factors (C/EBPβ and Stat3) display features of initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ and Stat3 is sufficient to reprogram neural stem cells along the aberrant mesenchymal lineage, while simultaneously suppressing differentiation along the default neural lineages (neuronal and glial). Conversely, silencing the two transcription factors in human glioma cell lines and glioblastoma-derived tumor initiating cells leads to collapse of the mesenchymal signature with corresponding loss of tumor aggressiveness in vitro and in immunodeficient mice after intracranial injection. In human tumor samples, combined expression of C/EBPβ and Stat3 correlates with mesenchymal differentiation of primary glioma and is a predictor of poor clinical outcome. Taken together, these results reveal that activation of a small regulatory module – inferred from the accurate reconstruction of transcriptional networks – is necessary and sufficient to initiate and maintain an aberrant phenotypic state in eukaryotic cells.
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| Overall design |
SNB19 human glioma cells and GBM-derived brain tumor initiating cells were transduced with STAT3 and CEBPB shRNA lentiviral vectors.
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| Contributor(s) |
Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, Sulman EP, Anne SL, Doetsch F, Colman H, Lasorella A, Aldape K, Califano A, Iavarone A |
| Citation(s) |
20032975 |
| Submission date |
Nov 20, 2009 |
| Last update date |
Aug 16, 2018 |
| Contact name |
Mariano Javier Alvarez |
| Organization name |
Columbia University
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| Department |
Systems Biology
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| Lab |
Systems Biology
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| Street address |
1130 St. Nicholas ave.
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10032 |
| Country |
USA |
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| Platforms (1) |
| GPL6947 |
Illumina HumanHT-12 V3.0 expression beadchip |
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| Samples (74)
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| This SubSeries is part of SuperSeries: |
| GSE20281 |
The transcriptional network for mesenchymal transformation of brain tumours |
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| Relations |
| BioProject |
PRJNA129055 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE19114_RAW.tar |
63.1 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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