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The transcriptional network for mesenchymal transformation of brain tumours

Nature volume 463, pages 318–325 (2010)Cite this article

Abstract

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.

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Figure 1: The mesenchymal signature of HGGs is controlled by six TFs.
Figure 2: A hierarchical transcriptional module regulates the MGES.
Figure 3: Ectopic expression of C/EBPβ and STAT3C in NSCs induces mesenchymal transformation and inhibits neural differentiation.
Figure 4: C/EBPβ and STAT3 maintain the mesenchymal phenotype of human glioma cells.
Figure 5: C/EBPβ and STAT3 are essential for glioma tumour aggressiveness in mice and humans.

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Primary accessions

Gene Expression Omnibus

Data deposits

Gene expression data have been deposited in Gene Expression Omnibus (GEO) with the following accession numbers: GSE19113 for mouse and GSE19114 for human data.

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Acknowledgements

This work was supported by National Institute of Health grants R01CA109755 (A.C.), R01CA101644 (A.L.), R01CA085628 and R01NS061776 (A.I.), NCI Grand Opportunities TDDN Network 1RC2CA148308-01 (A.C.), In Silico Research Centre of Excellence NCI-caBIG 29XS192 (A.C.), National Centers for Biomedical Computing NIH Roadmap Initiative U54CA121852 (A.C.) and National Institute of General Medical Sciences grant P20GM075059 (E.Y.S.). M.S.C. is supported by a fellowship from the Italian Ministry of Welfare/Provincia di Benevento and S.L.A. by a fellowship from Fondation de Recherche Medicale. We thank N. Ramirez-Martinez for technical assistance with mouse husbandry and in vivo procedures.

Author Contributions A.C. and A.I. conceived the ideas for this study. A.C. designed the computational systems biology approach and A.I. the experimental platform. M.S.C. prepared constructs, performed the biochemical experiments and the microarrays, conducted biological experiments and analyses, assisted in mouse intracranial injections and performed tumour xenograft immunohistochemistry and tumour analysis. W.K.L. performed reverse engineering, master regulator, and statistical analyses. M.J.A. conducted gene expression, bioinformatics and statistical analyses. R.J.B. and E.Y.S. provided experimental material. X.Z. and F.D. assisted in mouse intracranial injections. E.P.S., H.C. and K.A. provided reagents, performed the arrayCGH/expression analysis and primary human tumour immunohistochemistry. S.L.A. performed cell culture immunofluorescence microscopy and analysis. A.L. assisted in primary NSC experiments, performed intracranial injections and assisted in the analysis of mouse xenografts. A.I. and A.C. wrote the manuscript with contributions from all other authors. M.S.C., W.K.L. and M.J.A. contributed equally to this work.

Author information

Author notes

  1. Maria Stella Carro, Wei Keat Lim & Sandrine L. Anne

    Present address: 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.).,

  2. Maria Stella Carro, Wei Keat Lim and Mariano Javier Alvarez: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Cancer Genetics,,

    Maria Stella Carro, Xudong Zhao, Sandrine L. Anne, Anna Lasorella, Andrea Califano & Antonio Iavarone

  2. Department of Biomedical Informatics,,

    Wei Keat Lim & Andrea Califano

  3. Center for Computational Biology and Bioinformatics,,

    Wei Keat Lim, Mariano Javier Alvarez & Andrea Califano

  4. Joint Centers for Systems Biology,,

    Mariano Javier Alvarez & Andrea Califano

  5. Department of Pathology,,

    Fiona Doetsch, Anna Lasorella & Antonio Iavarone

  6. Department of Pediatrics,,

    Anna Lasorella

  7. Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA,

    Antonio Iavarone

  8. Department of Neurosurgery, New York University School of Medicine & NYU Langone Medical Center, New York, New York 10016, USA,

    Robert J. Bollo

  9. Burnham Institute for Medical Research, La Jolla, California 92037, USA ,

    Evan Y. Snyder

  10. Division of Radiation Oncology,,

    Erik P. Sulman

  11. Department of Neuro-Oncology,,

    Howard Colman

  12. Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA,

    Ken Aldape

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  1. Maria Stella Carro
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Corresponding authors

Correspondence to Andrea Califano or Antonio Iavarone.

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Carro, M., Lim, W., Alvarez, M. et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318–325 (2010). https://doi.org/10.1038/nature08712

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