Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility

Silvia Giampieri, Cerys Manning, Steven Hooper, Louise Jones, Caroline S Hill, Erik Sahai

Research output: Contribution to journalArticlepeer-review

509 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1287-1296
Number of pages10
JournalNature Cell Biology
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 2009

Keywords

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

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