CREB Drives Acinar to Ductal Cells 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 and fibrotic inflammation activating 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 polymerase chain reaction. Single-cell RNA sequencing was performed in ACP-induced KC mice. Lineage tracing analysis using 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/pancreatic intraepithelial neoplasia 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 pancreatic intraepithelial neoplasia development, restrained tumor progression, and improved acinar cell function. CONCLUSIONS: Our findings demonstrate that CREB and Kras∗ promote irreversible acinar-to-ductal metaplasia, accelerating pancreatic cancer progression with ACP. Targeting CREB may present a promising strategy to mitigate inflammation-driven pancreatic tumorigenesis.