CREB drives acinar cells to ductal reprogramming and promotes pancreatic cancer progression in preclinical models of alcoholic pancreatitis

BACKGROUND & AIMS Chronic alcoholism often leads to pancreatitis, which exacerbates pancreatic damage through acinar cell injury, fibrotic inflammation and activates AKT/mTOR/cyclic adenosine monophosphate response element binding protein 1 (CREB) signaling axis. However, the molecular interplay between oncogenic Kras G12D/+ ( Kras* ) and CREB in promoting pancreatic cancer progression under chronic inflammation remains poorly understood. METHODS Experimental alcoholic chronic pancreatitis (ACP) induction was established in multiple mouse models, with euthanasia during the recovery stage to evaluate tumor latency. CREB was selectively deleted ( Creb fl/fl ) in Ptf1a CreERTM/+ ;LSL-Kras G12D/+ ( KC ) genetic mouse models ( KCC -/- ). Pancreata from Ptf1a CreERTM/+ , KC , and KCC -/- mice were analyzed using histological profiling, western blotting, phosphokinase array, and quantitative PCR. Single-cell RNA sequencing was performed in ACP-induced KC mice. Lineage tracing analysis in YFP reporter mice and acinar cell explant cultures analysis were also conducted. RESULTS ACP induction in KC mice significantly impaired pancreas’ repair mechanism. Acinar cell-derived ductal lesions demonstrated sustained CREB hyperactivation in acinar-to-ductal metaplasia (ADM)/pancreatic intraepithelial neoplasia (PanIN) lesions associated with pancreatitis and pancreatic cancer. Persistent CREB activity reprogrammed acinar cells, and increased profibrotic inflammation. Notably, acinar specific Creb deletion in ACP induced models suppressed high grade PanIN development, restrained tumor progression, and improved acinar cell function. CONCLUSIONS Our findings demonstrate that CREB and Kras* promote irreversible ADM, accelerating pancreatic cancer progression with ACP. Targeting CREB may present a promising strategy to mitigate inflammation-driven pancreatic tumorigenesis.