Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility.
TL;DR: It is demonstrated that TGFβ signalling is transiently and locally activated in motile single cells and essential for blood-borne metastasis as breast cancer cells spread.
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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.
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Citations
Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer
Evanthia T. Roussos,Michele Balsamo,Shannon K. Alford,Jeffrey B. Wyckoff,Bojana Gligorijevic,Yarong Wang,Maria Pozzuto,Robert Stobezki,Sumanta Goswami,Jeffrey E. Segall,Douglas A. Lauffenburger,Anne R. Bresnick,Frank B. Gertler,John S. Condeelis +13 more
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