Mechanisms Underlying Metastatic Pancreatic Cancer

Pancreatic ductal adenocarcinoma is an overwhelming fatal disease that often presents with overt metastases and ultimately causes the majority of cancer-associated deaths. The mechanisms underlying the metastatic cascade are complex, and research in recent years has begun to provide insights into the underlying drivers of this phenomenon. It has become clear that cancer cells, in particular pancreatic cancer cells, possess properties of plasticity involving bidirectional transition between epithelial and mesenchymal identities. Furthermore, recent work has begun to establish that there are distinct hybrid states between purely epithelial and purely mesenchymal states that cancer cells may reside, in order to thrive at different stages of carcinogenesis. We discuss how this plasticity is important for different phases of the metastatic cascade, from delamination to colonization, and how different epithelial-mesenchymal states may affect metastatic organotropism. In this review, we summarize the current understanding of pancreatic cancer cell plasticity and metastasis, and highlight current model systems that can be used to study these phenomena.