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Supplementary Materials and Methods from Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells

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posted on 2023-03-30, 23:47 authored by Morgane Bourcy, Meggy Suarez-Carmona, Justine Lambert, Marie-Emilie Francart, Hélène Schroeder, Céline Delierneux, Nicolas Skrypek, Erik W. Thompson, Guy Jérusalem, Geert Berx, Marc Thiry, Silvia Blacher, Brett G. Hollier, Agnès Noël, Cécile Oury, Myriam Polette, Christine Gilles

Supplementary Materials and Methods

Funding

Fonds De La Recherche Scientifique

Fondation Contre le Cancer

the “Partenariat Hubert Curien-Tournesol”, the “Fonds spéciaux de la Recherche” (University of Liège), the “Centre Anticancéreux près l'Université de Liège”, the “Fonds Léon Fredericq” (University of Liège), the “Direction Générale Opérationnelle de l'Economie”, de l'Emploi et de la Recherche from the Service Public de Wallonie (SPW, Belgium), the Interuniversity Attraction Poles Programme (Brussels, Belgium), the “Actions de Recherche Concertées”

Australian Government Department of Health

Movember Foundation

Prostate Cancer Foundation of Australia

National Breast Cancer Foundation

History

ARTICLE 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.

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