2. Academic Validation
  3. EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells

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

  • Nat Commun. 2017 Jun 12;8:15773. doi: 10.1038/ncomms15773.
Deepika Neelakantan 1 2,  Hengbo Zhou 1 3,  Michael U J Oliphant 1 4,  Xiaomei Zhang 5,  Lukas M Simon 6,  David M Henke 7,  Chad A Shaw 7,  Meng-Fen Wu 5,  Susan G Hilsenbeck 5 8,  Lisa D White 7 9,  Michael T Lewis 5 9,  Heide L Ford 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Colorado-Denver, 12800 East 19th Avenue, Room P18-6115, Aurora, Colorado 80045, USA.
  • 2 Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
  • 3 Cancer Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
  • 4 Integrated Physiology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
  • 5 Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 6 Institute of Computational Biology, Helmholtz Zentrum München (GmbH), Neuherberg 85764, Germany.
  • 7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 8 Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 9 Departments of Molecular and Cellular Biology and Radiology, Baylor College of Medicine, Houston, Texas 77030, USA.
PMID: 28604738 DOI: 10.1038/ncomms15773
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.

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