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The transcriptional network for mesenchymal transformation of brain tumours

Author

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  • Maria Stella Carro

    (Institute for Cancer Genetics,
    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.).)

  • Wei Keat Lim

    (Department of Biomedical Informatics,
    Center for Computational Biology and Bioinformatics,
    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.).)

  • Mariano Javier Alvarez

    (Center for Computational Biology and Bioinformatics,
    Joint Centers for Systems Biology,)

  • Robert J. Bollo

    (New York University School of Medicine & NYU Langone Medical Center, New York, New York 10016, USA)

  • Xudong Zhao

    (Institute for Cancer Genetics,)

  • Evan Y. Snyder

    (Burnham Institute for Medical Research, La Jolla, California 92037, USA)

  • Erik P. Sulman

    (Division of Radiation Oncology,)

  • Sandrine L. Anne

    (Institute for Cancer Genetics,
    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.).)

  • Fiona Doetsch

    (Department of Pathology,)

  • Howard Colman

    (Department of Neuro-Oncology,)

  • Anna Lasorella

    (Institute for Cancer Genetics,
    Department of Pathology,
    Department of Pediatrics,)

  • Ken Aldape

    (M.D. Anderson Cancer Center, Houston, Texas 77030, USA)

  • Andrea Califano

    (Institute for Cancer Genetics,
    Department of Biomedical Informatics,
    Center for Computational Biology and Bioinformatics,
    Joint Centers for Systems Biology,)

  • Antonio Iavarone

    (Institute for Cancer Genetics,
    Department of Pathology,
    Columbia University Medical Center, New York, New York 10032, USA)

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.

Suggested Citation

  • Maria Stella Carro & Wei Keat Lim & Mariano Javier Alvarez & Robert J. Bollo & Xudong Zhao & Evan Y. Snyder & Erik P. Sulman & Sandrine L. Anne & Fiona Doetsch & Howard Colman & Anna Lasorella & Ken A, 2010. "The transcriptional network for mesenchymal transformation of brain tumours," Nature, Nature, vol. 463(7279), pages 318-325, January.
    • Handle: RePEc:nat:nature:v:463:y:2010:i:7279:d:10.1038_nature08712
    DOI: 10.1038/nature08712
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    Cited by:

    1. Ida Larsson & Felix Held & Gergana Popova & Alper Koc & Soumi Kundu & Rebecka Jörnsten & Sven Nelander, 2024. "Reconstructing the regulatory programs underlying the phenotypic plasticity of neural cancers," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Yuyan Cheng & Yuqin Yin & Alice Zhang & Alexander M. Bernstein & Riki Kawaguchi & Kun Gao & Kyra Potter & Hui-Ya Gilbert & Yan Ao & Jing Ou & Catherine J. Fricano-Kugler & Jeffrey L. Goldberg & Zhigan, 2022. "Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    3. Marco Luciani & Chiara Garsia & Stefano Beretta & Ingrid Cifola & Clelia Peano & Ivan Merelli & Luca Petiti & Annarita Miccio & Vasco Meneghini & Angela Gritti, 2024. "Human iPSC-derived neural stem cells displaying radial glia signature exhibit long-term safety in mice," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    4. Lijing Yang & Lei Tu & Shilpa Bisht & Yiqing Mao & Daniel Petkovich & Sara-Jayne Thursby & Jinxiao Liang & Nibedita Patel & Ray-Whay Chiu Yen & Tina Largent & Cynthia Zahnow & Malcolm Brock & Kathy Ga, 2024. "Tissue-location-specific transcription programs drive tumor dependencies in colon cancer," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    5. Andrea Comba & Syed M. Faisal & Patrick J. Dunn & Anna E. Argento & Todd C. Hollon & Wajd N. Al-Holou & Maria Luisa Varela & Daniel B. Zamler & Gunnar L. Quass & Pierre F. Apostolides & Clifford Abel , 2022. "Spatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    6. Kriti Puniyani & Eric P Xing, 2013. "GINI: From ISH Images to Gene Interaction Networks," PLOS Computational Biology, Public Library of Science, vol. 9(10), pages 1-15, October.

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