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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition*
  • Female
  • Heterografts
  • Humans
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Metastasis*
  • Paracrine Communication*
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Tumor Microenvironment
  • Veratrum Alkaloids / pharmacology
  • Zinc Finger Protein GLI1 / antagonists & inhibitors
  • Zinc Finger Protein GLI1 / metabolism*

Substances

  • GANT 61
  • GLI1 protein, human
  • IPI-926
  • Pyridines
  • Pyrimidines
  • Veratrum Alkaloids
  • Zinc Finger Protein GLI1