Acinar-to-Ductal Metaplasia in Chronic Pancreatitis: A Critical Link Between Inflammation and Pancreatic Carcinogenesis

Abstract

Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder that results from the interplay of genetic, environmental, immune, and pathogenic factors. Traditionally characterized by irreversible pancreatic injury, CP is now recognized as an important precursor to pancreatic ductal adenocarcinoma (PDAC), a deadly form of pancreatic cancer. The persistent inflammatory microenvironment of CP promotes the accumulation of genetic mutations and cellular reprogramming, which can lead to acinar-to-ductal metaplasia (ADM), a precursor lesion of PDAC. ADM represents a reversible cellular reprogramming process, wherein pancreatic acinar cells transform into duct-like cells in response to inflammatory stress. This process is critical in both tissue repair and, under sustained inflammatory or oncogenic conditions, the progression to neoplasia. The molecular drivers of ADM include inflammatory cytokines, oxidative stress, extracellular matrix remodeling, and transcriptional reprogramming. Notably, the activation of signaling pathways such as Notch, EGFR/RAS/MAPK, and Wnt/β-catenin play pivotal roles in regulating ADM and its progression toward pancreatic cancer. Furthermore, the AKT/GSK3β signaling axis emerges as a central regulator in the modulation of ADM and its subsequent transition to malignancy. Understanding the molecular mechanisms of ADM and its interplay with pancreatic stellate cells provides valuable insights into therapeutic targets that could interrupt the progression from chronic pancreatitis to pancreatic cancer. This review highlights the pathophysiology of CP, the role of ADM in inflammation-driven pancreatic carcinogenesis, and the signaling networks involved in this process. By examining the regulatory pathways that govern ADM, this article aims to provide a framework for future therapeutic strategies that could target ADM and delay the progression of CP to PDAC. Early intervention in the ADM process, particularly in its reversible stages, presents a promising approach for preserving acinar cell function, preventing fibrosis, and ultimately reducing the risk of pancreatic cancer.