Acinar cell plasticity and subtype specification during acinar-to-ductal metaplasia and pancreatic cancer progression

The onset and progression of pancreatic ductal adenocarcinoma (PDAC) influence acinar cells, leading to metaplastic and neoplastic adaptations. Lineage tracing experiments demonstrate the inherent plasticity of pancreatic acinar cells towards various subtypes, including tuft cells (TCs), enteroendocrine cells, gastric pit-like cells, and senescent cells. These cell types contribute to the injury resolution and maintenance of tissue homeostasis. Further transition of certain acinar subtypes, such as TCs, into metaplastic neuroendocrine cells and neural-like progenitors results in an aggressive PDAC phenotype and poor prognosis. This review describes the factors driving the specification trajectory of pancreatic acinar cell subtypes, their metabolic and functional preferences, particularly in the context of tumor microenvironment (TME) modulation, and their utility as an attractive target for improved therapy response. We emphasize the roles of TME components, including cancer-associated fibroblasts, immune cells, cancer-associated mucins, and various signaling mediators, in acinar subtype specification. The review highlights the concept of acinar metaplastic duct heterogeneity and its implications for targeting aggressive acinar subtypes to improve survival outcomes.