Localized and Reversible TGFbeta Signalling Switches Breast Cancer Cells From Cohesive to Single Cell Motility

Nat Cell Biol. 2009 Nov;11(11):1287-96. doi: 10.1038/ncb1973. Epub 2009 Oct 18.

Abstract

Here we use intravital imaging to demonstrate a reversible transition to a motile state as breast cancer cells spread. Imaging primary tumours revealed heterogeneity in cell morphology and motility. Two distinct modes of motility were observed: collective and single-celled. By monitoring the localization of Smad2 and the activity of a TGFbeta-dependent reporter gene during breast cancer cell dissemination, we demonstrate that TGFbeta signalling is transiently and locally activated in motile single cells. TGFbeta1 switches cells from cohesive to single cell motility through a transcriptional program involving Smad4, EGFR, Nedd9, M-RIP, FARP and RhoC. Blockade of TGFbeta signalling prevented cells moving singly in vivo but did not inhibit cells moving collectively. Cells restricted to collective invasion were capable of lymphatic invasion but not blood-borne metastasis. Constitutive TGFbeta signalling promoted single cell motility and intravasation but reduced subsequent growth in the lungs. Thus, transient TGFbeta signalling is essential for blood-borne metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Female
  • Humans
  • Lymphatic Metastasis
  • Neoplasm Metastasis*
  • Signal Transduction*
  • Smad2 Protein / metabolism
  • Transforming Growth Factor beta / metabolism*

Substances

  • Smad2 Protein
  • Transforming Growth Factor beta