CREB activation drives acinar to ductal reprogramming and promote pancreatic cancer progression in animal models of alcoholic chronic pancreatitis

Abstract

AbstractBACKGROUND AND AIMSIn vivoinduction of alcoholic chronic pancreatitis (ACP) causes significant acinar damage, increased fibroinflammatory response, and heightened activation of cyclic response element binding protein 1 (CREB) when compared with alcohol (A) or chronic pancreatitis (CP) mediated pancreatic damage. However, the study elucidating the cooperative interaction between CREB and the oncogenicKrasG12D/+(Kras*) in promoting pancreatic cancer progression with ACP remains unexplored.METHODSExperimental ACP induction was established in multiple mouse models, followed by euthanization of the animals at various time intervals during the recovery periods. Tumor latency was determined in these mice cohorts. Here, we established CREB deletion (Crebfl/fl) inPtf1aCreERTM/+;LSL-KrasG12D+/−(KC) genetic mouse models (KCC−/−). Western blot, phosphokinase array, and qPCR were used to analyze the pancreata ofPtf1aCreERTM+/−,KCandKCC−/−mice. The pancreata of ACP-inducedKCmice were subjected to single-cell RNA sequencing (scRNAseq). Further studies involved conducting lineage tracing and acinar cell explant cultures.RESULTSACP induction inKCmice had detrimental effects on the pancreatic damage repair mechanism. The persistent existence of acinar cell-derived ductal lesions demonstrated a prolonged state of hyperactivated CREB. Persistent CREB activation leads to acinar cell reprogramming and increased pro-fibrotic inflammation inKCmice. Acinar-specificCrebablation reduced advanced PanINs lesions, hindered tumor progression, and restored acinar cell function in ACP-induced mouse models.CONCLUSIONSOur findings demonstrate that CREB cooperates withKras*to perpetuate an irreversible ADM and PanIN formation. Moreover, CREB sustains oncogenic activity to promote the progression of premalignant lesions toward cancer in the presence of ACP.