Tissue factor induced by epithelial-mesenchymal transition triggers a procoagulant state that drives metastasis of circulating tumor cells

Bourcy, Morgane, Suarez-Carmona, Meggy, Lambert, Justine, Francart, Marie-Emilie, Schroeder, Hélène, Delierneux, Céline, Skrypek, Nicolas, Thompson, Erik W., Jerusalem, Guy, Berx, Geert, Thiry, Marc, Blacher, Silvia, Hollier, Brett G., Noel, Agnès, Oury, Cécile, Polette, Myriam, & Gilles, Christine (2016) Tissue factor induced by epithelial-mesenchymal transition triggers a procoagulant state that drives metastasis of circulating tumor cells. Cancer Research, 76(14), pp. 4270-4282.

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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); 1-13. (c)2016 AACR.

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ID Code: 97701
Item Type: Journal Article
Refereed: Yes
DOI: 10.1158/0008-5472.can-15-2263
ISSN: 0008-5472
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2016 American Association for Cancer Research
Deposited On: 31 Jul 2016 23:21
Last Modified: 01 Aug 2016 22:19

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