Localised and reversible TGFβ signalling switches breast cancer cells from cohesive to single cell motility

Here we use intravital imaging to demonstrate a reversible transition to a motile state as breast cancer cells spread. Imaging primary tumours reveals heterogeneity in cell morphology and motility. Two distinct modes of motility are observed: collective and single-celled. By monitoring the localisation of Smad2 and the activity of a TGFβ-dependent reporter gene during breast cancer cell dissemination we demonstrate that TGFβ signalling is transiently and locally activated in motile single cells. TGFβ1 switches cells from cohesive to single cell motility through a transcriptional programme involving Smad4, EGFR, Nedd9, M-RIP, FARP and RhoC. Blockade of TGFβ signalling prevents cells moving singly in vivo but does not inhibit cells moving collectively. Cells restricted to collective invasion are capable of lymphatic invasion but not blood-borne metastasis. Constitutive TGFβ signalling promotes single cell motility and intravasation but reduces subsequent growth in the lungs. Thus, transient TGFβ signalling is critical for blood-borne metastasis.