Integrin regulation by tissue factor promotes cancer stemness and metastatic dissemination in breast cancer

Abstract

Tissue Factor (TF) is the initiator of blood coagulation but also functions as a signal transduction receptor. TF expression in breast cancer is associated with higher tumor grade, metastasis and poor survival. The role of TF signaling on the early phases of metastasis has never been addressed. Here, we show an association between TF expression and metastasis as well as cancer stemness in 574 breast cancer patients. In preclinical models, blockade of TF signaling inhibited metastasis tenfold independent of primary tumor growth. TF blockade caused a reduction in epithelial-to-mesenchymal-transition, cancer stemness and expression of the pro-metastatic markers Slug and SOX9 in several breast cancer cell lines and in ex vivo cultured tumor cells. Mechanistically, TF forms a complex with β1-integrin leading to inactivation of β1-integrin. Inhibition of TF signaling induces a shift in TF-binding from α3β1-integrin to α6β4 and dictates FAK recruitment, leading to reduced epithelial-to-mesenchymal-transition and tumor cell differentiation. In conclusion, TF signaling inhibition leads to reduced pro-metastatic transcriptional programs, and a subsequent integrin β1 and β4-dependent reduction in metastasic dissemination.

TF/PAR2 Signaling Axis Supports the Protumor Effect of Neutrophil Extracellular Traps (NETs) on Human Breast Cancer Cells

“…More recently, it was observed that the transmembrane glycoprotein CD44, a cancer stem cell (CSC) marker, which is also associated with EMT, regulates the expression of TF in breast cancer cells, resulting in enhanced tumor cell procoagulant activity and metastatic dissemination [ 19 ]. TF can also induce EMT, corroborating the evidence that there is a linkage between them [ 20 ]. Blocking of the TF signaling with a monoclonal anti-human TF antibody reduced EMT and CSC programs in breast cancer cells, affecting cell invasion and spheroid formation [ 20 ].…”

“…TF can also induce EMT, corroborating the evidence that there is a linkage between them [ 20 ]. Blocking of the TF signaling with a monoclonal anti-human TF antibody reduced EMT and CSC programs in breast cancer cells, affecting cell invasion and spheroid formation [ 20 ].…”

“…Further, in breast cancer patients, TF expression was shown to be increased in both primary tumor and plasma samples compared to normal controls, pointing to an important role in breast cancer progression [ 8 ]. Ünlü and colleagues recently demonstrated that TF inhibition in breast cancer cells reduces EMT activation [ 20 ]. In this context, the blockade of TF signaling with a monoclonal antibody impaired EMT activation in vitro and reduced metastasis in vivo [ 20 ].…”

“…Ünlü and colleagues recently demonstrated that TF inhibition in breast cancer cells reduces EMT activation [ 20 ]. In this context, the blockade of TF signaling with a monoclonal antibody impaired EMT activation in vitro and reduced metastasis in vivo [ 20 ].…”

Coagulation and platelet biology at the intersection of health and disease: illustrated capsules of the 11th Symposium on Hemostasis at the University of North Carolina

“…Thus, TF affects early onset of metastasis by affecting cancer stemness via regulation of the expression and function of β 1 and β 4 integrins. For details, see [ 17 ]. FAK, focal adhesion kinase; mAb, monoclonal antibody.…”