Justine Lambert

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

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.

Epithelial‐Mesenchymal Plasticity and Circulating Tumor Cells: Travel Companions to Metastases

Epithelial–mesenchymal transitions (EMTs) associated with metastatic progression may contribute to the generation of hybrid phenotypes capable of plasticity. This cellular plasticity would provide tumor cells with an increased potential to adapt to the different microenvironments encountered during metastatic spread. Understanding how EMT may functionally equip circulating tumor cells (CTCs) with an enhanced competence to survive in the bloodstream and niche in the colonized organs has thus become a major cancer research axis. We summarize here clinical data with CTC endpoints involving EMT. We then review the work functionally linking EMT programs to CTC biology and deciphering molecular EMT‐driven mechanisms supporting their metastatic competence. Developmental Dynamics 247:432–450, 2018.