Abstract LB-147: EMT transcription factors induce tissue factor expression and pro-coagulant properties, supporting early metastasis of circulating tumor cells

Abstract

Abstract The presence of circulating tumor cells (CTCs) expressing traits of epithelial-mesenchymal transition (EMT) in cancer patients is increasingly recognized. Recently, we identified a new mechanism by which EMT induces the expression of Tissue Factor (TF, a major cell-associated initiator of coagulation), triggering a local activation of the coagulation cascade that favors the early metastatic colonization of EMT-positive CTCs (Bourcy et al., Cancer Research, 2016). Strengthening the functional contribution of EMT to TF regulation and coagulation, we further accumulated evidence that EMT transcription factors regulate TF expression. Thus, silencing ZEB1 inhibited both EMT-associated TF expression and coagulant activity. EMT-positive cells also exhibited a higher survival/persistence in lungs of mice colonized after intravenous injection, which was diminished by silencing ZEB1. Inversely, triggering de novo expression of Snail in MDA-MB-468 increased TF, coagulant properties and early metastasis in mice. Using TF promoter reporter vectors (mutated at different potential ZEB1 and Snail transcription factors) and CHIP, we further identified a binding region for ZEB1 in the proximal TF promoter encompassing a MCAT box, suggesting that ZEB1 and YAP might interact to regulate TF expression. Ongoing experiments are being performed to verify this hypothesis. We also collected data suggesting that targeting this new EMT/TF axis with anti-EMT drugs may represent an important extension to global anticoagulant strategies against cancer. Citation Format: Morgane Bourcy, Nicolas Skrypek, Erik W. Thompson, Geert Berx, Brett Hollier, Myriam Polette, Christine Gilles. EMT transcription factors induce tissue factor expression and pro-coagulant properties, supporting early metastasis of circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-147. doi:10.1158/1538-7445.AM2017-LB-147