Systems biology: Network spreading
Identification of a small transcription factor network that is responsible for the mesenchymal behavior of glioma cells.
High-grade gliomas, such as glioblastoma, are incurable partly because the tumour cells are widely disseminated throughout the brain. This capacity for invasive growth has been associated with the expression of genes more commonly transcribed in mesenchymal cells. Antonio Iavarone, Andrea Califano and colleagues have identified a small transcription factor network that is responsible for the mesenchymal behaviour of glioma cells.
The authors applied a specific algorithm designed to infer causal transcription factor–target interactions to gene expression profiles from 176 samples of high-grade gliomas. They analysed the resulting interactome with a new algorithm that enabled them to evaluate the transcription factor network in terms of a previously identified mesenchymal gene expression signature from high-grade gliomas. This identified 53 transcription factors that are associated with regulating mesenchymal gene expression, and further analyses identified signal transducer and activator of transcription 3 (STAT3) and CAATT/enhancer binding protein- (CEBP) as potential master regulators that control the expression of a substantial proportion of these mesenchymal genes.
In vitro analyses were used to confirm that both STAT3 and CEBP bound promoters of mesenchymal genes and that they could regulate their own expression as well as that of genes encoding other transcription factors, such as FOSL2, RUNX1 and bHLH-B2, which also regulate several mesenchymal genes. These data were used to establish that STAT3 and CEBP are at the top of a small transcriptional module that is responsible for the expression of most mesenchymal genes in high-grade glioma cells.
Expression of STAT3 and CEBP in mouse neural stem cells resulted inreprogramming of these cells in favour of a fibroblast-like morphology, invasive growth in wound healing assays and the expression of mesenchymal markers. Conversely, knock down of both STAT3 and CEBP in mouse glioblastoma-initiating cells resulted in loss of mesenchymalgene and protein expression, inhibition of invasive growth and markedly reduced tumour growth in immunocompromized mice. Moreover, immunohistochemicalanalyses of a small number of human glioblastoma samples for which outcome data were available indicated that the expression of both active STAT3 and CEBP is significantly associated with a mesenchymal phenotype and a poorer prognosis.
The authors conclude that systems biology approaches can be used to identify master transcription factors that are involved in malignant transformation, and such approaches could be applied to help dissect the complexity of other tumour phenotypes.
Nicola McCarthy
References
- Carro, M. S. et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318–325 (2009). | Article | PubMed |
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