Antibody-based targeting of alternatively spliced tissue factor: A new approach to impede the primary growth and spread of pancreatic ductal adenocarcinoma
AuthorUnruh, Dusten; Ünlü, Betü; Lewis, Clayton S.; Qi, Xiaoyang; Chu, Zhengtao; Sturm, Robert; Keil, Ryan; Ahmad, Syed A.; Sovershaev, Timofey; Adam, Mariette; Van Dreden, Patrick; Woodhams, Barry J.; Ramchandani, Divya; Weber, Georg F.; Rak, Janusz W.; Wolberg, Alisa S.; Mackman, Nigel; Versteeg, Henri H.; Bogdanov, Vladimir Y.
Alternatively spliced Tissue Factor (asTF) is a secreted form of Tissue Factor (TF), the trigger of blood coagulation whose expression levels are heightened in several forms of solid cancer, including pancreatic ductal adenocarcinoma (PDAC). asTF binds to β1 integrins on PDAC cells, whereby it promotes tumor growth, metastatic spread, and monocyte recruitment to the stroma. In this study, we determined if targeting asTF in PDAC would significantly impact tumor progression. We here report that a novel inhibitory anti-asTF monoclonal antibody curtails experimental PDAC progression. Moreover, we show that tumor-derived asTF is able to promote PDAC primary growth and spread during early as well as later stages of the disease. This raises the likelihood that asTF may comprise a viable target in early- and late-stage PDAC. In addition, we show that TF expressed by host cells plays a significant role in PDAC spread. Together, our data demonstrate that targeting asTF in PDAC is a novel strategy to stem PDAC progression and spread.