Pancreatic ductal metaplasia (PDM) is the step-wise replacement of differentiated somatic cells with ductal or ductal-like cells in the pancreas. PDM is usually triggered by cellular and environmental insults. PDM development may involve all cell lineages of the pancreas, and acinar cells with the highest plasticity are the major source of PDM. Pancreatic progenitor cells are also involved as cells of origin or transitional intermediates. PDM is heterogeneous at histological, cellular and molecular levels and only certain subsets of PDM develop further into pancreatic intraepithelial neoplasia (PanIN) and then pancreatic ductal adenocarcinoma (PDAC). The formation and evolution of PDM is regulated at cellular and molecular levels through a complex network of signaling pathways. The key molecular mechanisms that drive PDM formation and its progression into PanIN/PDAC remain unclear but represent key targets for reversing or inhibiting PDM. Alternatively, PDM could be a source of pancreas regeneration, including both exocrine and endocrine components. Cellular aging and apoptosis are obstacles to PDM-to-PanIN progression or pancreas regeneration. Functional identification of the cellular and molecular events driving senescence and apoptosis in PDM and its progression would help not only to restrict the development of PDM into PanIN/PDAC, but may also facilitate pancreatic regeneration. This review systematically assesses recent advances in the understanding of PDM physiology and pathology with a focus on its implications for enhancing regeneration and prevention of cancer.

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