Tissue factor drives pancreatic ductal adenocarcinoma invasion and metastasis and is therapeutically targeted by hydroxygenkwanin

Cancer-associated thrombosis is one of the most common causes of morbidity and mortality in patients with pancreatic ductal adenocarcinoma (PDAC). However, this knowledge has not yet produced any significant advances in treating cancer. Tissue factor (TF), also known as coagulation factor III, is the main activator of the coagulation cascade, its exact role in metastasis is unclear. The present study demonstrates that TF is highly expressed in PDAC tissue and is associated with advanced Tumor-Node-Metastasis (TNM) stage and poor patient survival. In vitro and in vivo models showed that TF overexpression promoted PDAC cell invasion and metastasis, while TF knockdown inhibited this malignant phenotype. RNA-seq and Co-IP showed that TF promoted tumor progression by activating the NF-κB signaling pathway via protease-activated receptor (PAR2). We also identified the TF-suppressing agent hydroxygenkwanin (HGK) as an effective therapeutic agent that inhibited TF-mediated tumor metastasis in mouse models. Our results identified TF as a key driver of PDAC metastasis via the NF-κB pathway. Therefore, we propose that HGK is a potential therapeutic for inhibiting tumor invasion and metastasis.