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EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells

Author

Listed:
  • Deepika Neelakantan

    (University of Colorado–Denver
    Molecular Biology Program, University of Colorado Anschutz Medical Campus)

  • Hengbo Zhou

    (University of Colorado–Denver
    Cancer Biology Program, University of Colorado Anschutz Medical Campus)

  • Michael U. J. Oliphant

    (University of Colorado–Denver
    Integrated Physiology Program, University of Colorado Anschutz Medical Campus)

  • Xiaomei Zhang

    (Lester and Sue Smith Breast Center, Baylor College of Medicine)

  • Lukas M. Simon

    (Institute of Computational Biology, Helmholtz Zentrum München (GmbH))

  • David M. Henke

    (Baylor College of Medicine)

  • Chad A. Shaw

    (Baylor College of Medicine)

  • Meng-Fen Wu

    (Lester and Sue Smith Breast Center, Baylor College of Medicine)

  • Susan G. Hilsenbeck

    (Lester and Sue Smith Breast Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Lisa D. White

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Michael T. Lewis

    (Lester and Sue Smith Breast Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Heide L. Ford

    (University of Colorado–Denver
    Molecular Biology Program, University of Colorado Anschutz Medical Campus
    Cancer Biology Program, University of Colorado Anschutz Medical Campus
    Integrated Physiology Program, University of Colorado Anschutz Medical Campus)

Abstract

Recent fate-mapping studies concluded that EMT is not required for metastasis of carcinomas. Here we challenge this conclusion by showing that these studies failed to account for possible crosstalk between EMT and non-EMT cells that promotes dissemination of non-EMT cells. In breast cancer models, EMT cells induce increased metastasis of weakly metastatic, non-EMT tumour cells in a paracrine manner, in part by non-cell autonomous activation of the GLI transcription factor. Treatment with GANT61, a GLI1/2 inhibitor, but not with IPI 926, a Smoothened inhibitor, blocks this effect and inhibits growth in PDX models. In human breast tumours, the EMT-transcription factors strongly correlate with activated Hedgehog/GLI signalling but not with the Hh ligands. Our findings indicate that EMT contributes to metastasis via non-cell autonomous effects that activate the Hh pathway. Although all Hh inhibitors may act against tumours with canonical Hh/GLI signalling, only GLI inhibitors would act against non-canonical EMT-induced GLI activation.

Suggested Citation

  • Deepika Neelakantan & Hengbo Zhou & Michael U. J. Oliphant & Xiaomei Zhang & Lukas M. Simon & David M. Henke & Chad A. Shaw & Meng-Fen Wu & Susan G. Hilsenbeck & Lisa D. White & Michael T. Lewis & Hei, 2017. "EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells," Nature Communications, Nature, vol. 8(1), pages 1-14, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15773
    DOI: 10.1038/ncomms15773
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    Cited by:

    1. Connor J. Hughes & Kaiah M. Fields & Etienne P. Danis & Jessica Y. Hsu & Deepika Neelakantan & Melanie Y. Vincent & Annika L. Gustafson & Michael J. Oliphant & Varsha Sreekanth & Vadym Zaberezhnyy & J, 2023. "SIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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