title: Tissue Factor Induced by Epithelial-Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells.
abstract: Epithelial-mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific microenvironment for tumor cells, we explored a potential link between EMT and coagulation that may provide EMT-positive CTCs with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related procoagulant properties in the blood. TF blockade by antibody or shRNA diminished the procoagulant activity of EMT-positive cells, confirming a functional role for TF in these processes. Silencing the EMT transcription factor ZEB1 inhibited both EMT-associated TF expression and coagulant activity, further strengthening the link between EMT and coagulation. Accordingly, EMT-positive cells exhibited a higher persistance/survival in the lungs of mice colonized after intravenous injection, a feature diminished by TF or ZEB1 silencing. In tumor cells with limited metastatic capability, enforcing expression of the EMT transcription factor Snail increased TF, coagulant properties, and early metastasis. Clinically, we identified a subpopulation of CTC expressing vimentin and TF in the blood of metastatic breast cancer patients consistent with our observations. Overall, our findings define a novel EMT-TF regulatory axis that triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTCs. Cancer Res; 76(14); 4270-82. ©2016 AACR.
authors.affiliation: GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium.
authors.forename: Morgane
authors.initials: M
authors.lastname: Bourcy
authors.affiliation: GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium.
authors.forename: Meggy
authors.initials: M
authors.lastname: Suarez-Carmona
authors.affiliation: GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium.
authors.forename: Justine
authors.initials: J
authors.lastname: Lambert
authors.affiliation: GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium.
authors.forename: Marie-Emilie
authors.initials: ME
authors.lastname: Francart
authors.affiliation: CHU, Department of Medical Oncology, University of Liège, Liège, Belgium.
authors.forename: Hélène
authors.initials: H
authors.lastname: Schroeder
authors.affiliation: GIGA-Cardiovascular Sciences, Laboratory of Thrombosis and Hemostasis, University of Liège, Liège, Belgium.
authors.forename: Céline
authors.initials: C
authors.lastname: Delierneux
authors.affiliation: Unit of Molecular and Cellular Oncology Lab, Inflammation Research Center, VIB, Ghent, Belgium. Department of Biomedical Molecular Biology, Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skrypek
authors.affiliation: Institute of Health and Biomedical Innovation and School of Biomedical Sciences Translational Research Institute, Queensland University of Technology, Brisbane, Australia.
authors.forename: Erik W
authors.initials: EW
authors.lastname: Thompson
authors.affiliation: CHU, Department of Medical Oncology, University of Liège, Liège, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Jérusalem
authors.affiliation: Unit of Molecular and Cellular Oncology Lab, Inflammation Research Center, VIB, Ghent, Belgium. Department of Biomedical Molecular Biology, Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Berx
authors.affiliation: GIGA-Neurosciences, Unit of Cell and Tissue Biology, University of Liège, Liège, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Thiry
authors.affiliation: GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia.
authors.forename: Brett G
authors.initials: BG
authors.lastname: Hollier
authors.affiliation: GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
authors.affiliation: GIGA-Cardiovascular Sciences, Laboratory of Thrombosis and Hemostasis, University of Liège, Liège, Belgium.
authors.forename: Cécile
authors.initials: C
authors.lastname: Oury
authors.affiliation: INSERM UMR-S 903, CHU, Biopathology Laboratory, University of Reims, Reims, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Polette
authors.affiliation: GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium. cgilles@ulg.ac.be.
authors.forename: Christine
authors.initials: C
authors.lastname: Gilles
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D013925:Thromboplastin / Q000096:biosynthesis*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000502:physiology
chemical_list: C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D013925:Thromboplastin