TFAP2A enhances tumor stemness and promotes metastasis in pancreatic ductal adenocarcinoma

Metastasis is the leading cause of death for nearly 90% of patients with cancer. In the digestive system, malignancies preferentially metastasize to the liver, which occurs in 76-80% of patients with pancreatic ductal adenocarcinoma (PDAC). Given the shared endoderm origin of embryonic pancreas and liver, this study investigated whether genes highly expressed in liver progenitors drive PDAC cells metastasize to the liver. Using an <i>in vitro</i> liver differentiation model, genes highly expressed in liver progenitors were identified. Among them, TFAP2A was highly expressed in PDAC and closely related to PDAC liver metastasis. Cancer associated fibroblasts (CAFs) upregulated TFAP2A expression by bone morphogenetic protein 4 (BMP4). Functional experiments demonstrated that TFAP2A overexpression promoted PDAC cell stemness and liver metastasis <i>in vitro</i> and <i>in vivo</i>. Mechanistically, TFAP2A could promote epithelial mesenchymal transition (EMT) and recruit macrophage by upregulating MYC, facilitating PDAC cell intravasation. Collectively, these findings unveil molecular mechanisms for PDAC liver metastasis and potential therapeutic targets.