Localized 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 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 TGF beta-dependent reporter gene during breast cancer cell dissemination, we demonstrate that TGF beta signalling is transiently and locally activated in motile single cells. TGF beta 1 switches cells from cohesive to single cell motility through a transcriptional program involving Smad4, EGFR, Nedd9, M-RIP, FARP and RhoC. Blockade of TGF beta 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 TGF beta signalling promoted single cell motility and intravasation but reduced subsequent growth in the lungs. Thus, transient TGF beta signalling is essential for blood-borne metastasis.