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

Objective: Alcoholic chronic pancreatitis (ACP) exacerbates pancreatic damage through acinar cell injury, fibroinflammation, and cyclic adenosine monophosphate response element binding protein 1 (CREB) activation, surpassing the damage by alcohol (A) alone or cerulein-induced CP. The molecular cooperativity between CREB and oncogenic Kras G12D/+ ( Kras* ) in promoting pancreatic cancer progression within the context of ACP remains unclear.

Methods: Experimental ACP induction was established in multiple mouse models, with euthanasia during the recovery stage to assess tumor latency. We established CREB deletion ( 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 western blotting, phosphokinase array, and quantitative PCR. Single-cell RNA sequencing was performed in ACP-induced KC mice. Lineage tracing of acinar cell explant cultures and analysis of tissue samples from human pancreatic diseases (CP and pancreatic ductal adenocarcinoma [PDAC]) were conducted.

Results: ACP induction in KC mice impaired the pancreas' repair mechanism. Acinar cell- derived ductal lesions demonstrated prolonged hyperactivated CREB in acinar-to-ductal metaplasia (ADM)/pancreatic intraepithelial neoplasia (PanIN) lesions associated with pancreatitis and in PDAC. Persistent CREB activation reprogrammed acinar cells, increasing profibrotic inflammation. In ACP-induced models, acinar-specific Creb ablation reduced advanced PanIN lesions, hindered tumor progression, and improved acinar cell function. Pharmacological targeting of CREB significantly reduced the primary tumor burden in a PDAC mouse model with ACP.

Conclusions: Our findings demonstrate that CREB and Kras* promote irreversible ADM, accelerating pancreatic cancer progression with ACP. Targeting CREB offers a promising strategy to address the clinical need for effective treatments for inflammation-driven pancreatic cancer.