CREB Drives Acinar to Ductal Cells Reprogramming and Promotes Pancreatic Cancer Progression in Preclinical Models of...

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.

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.

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.

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.