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

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 () and Heide L. Ford ()
Additional contact information
Deepika Neelakantan: University of Colorado–Denver
Hengbo Zhou: University of Colorado–Denver
Michael U. J. Oliphant: University of Colorado–Denver
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
Lisa D. White: Baylor College of Medicine
Michael T. Lewis: Lester and Sue Smith Breast Center, Baylor College of Medicine
Heide L. Ford: University of Colorado–Denver

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15773

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DOI: 10.1038/ncomms15773

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