Deciphering the liver’s role in pancreatic cancer metastasis: pathways and therapeutic approaches

The liver frequently serves as a site for metastasis in pancreatic ductal adenocarcinoma (PDAC), attributable to its extensive blood supply and supportive microenvironment, which fosters the formation of a pre-metastatic niche that facilitates tumor dissemination. Deciphering the mechanisms underlying niche formation has historically been challenging, requiring detailed investigation into the interactions between primary tumors and metastatic sites. Although these interactions were previously poorly understood, recent advances have elucidated key pathways involved in this process. These insights have been enabled by cutting-edge techniques, including spatial histological mapping, single-cell sequencing, and the identification of novel molecular markers in pancreatic and hepatic metastases. Furthermore, this review revisits and critically evaluates Paget's 'seed and soil' hypothesis in light of current evidence from studies on liver metastatic niches. This review aims to deepen our understanding of liver metastasis in PDAC, with potential implications for the development of targeted therapies and improved clinical outcomes.