Box, E. W. | bioRxiv Science

bioRxiv2025

Targeting CREB remodels the immune microenvironment to enhance immunotherapy responses in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease in need of improved treatments. Cyclic adenosine monophosphate response element binding protein 1 (CREB) is an emerging therapeutic target whose oncogenic effects in PDAC have been largely attributed to a key molecular interplay between oncogenic KrasG12D/+ (Kras*) and chronic inflammation driving irreversible acinar to ductal reprogramming. Here, we demonstrate that CREB activation fosters tumor associated macrophage (TAM) mediated immunosuppression and promotes PDAC growth in an aggressive LSL-KrasG12D/+;Trp53R172H/+;Pdx1Cre/+(KPC) genetically engineered mouse model. Selective deletion of CREB (Crebfl/fl) in KPC(KPCC-/-) mice attenuates primary disease burden. Unbiased transcriptomic analysis and validation using diverse molecular, genetic and pharmacological approaches in vitro and in vivo identify CREB-mediated transcriptional regulation of leukemia inhibitory factor (Lif) as one of the potential mediators of tumor cell-macrophage crosstalk promoting a pro-tumor polarization of TAMs, thereby attenuating the infiltration of effector T cells. Mechanistically, cancer cell derived LIF facilitates an immunosuppressive, pro-tumorigenic state. Importantly, pharmacological targeting of the CREB-LIF signaling axis between cancer cells and macrophages, using a CREB-specific inhibitor (CREBi), significantly suppresses tumor growth and sensitizes PDAC to immunotherapy, highlighting the therapeutic potential of this treatment combination to improve outcomes in this aggressive disease.

cancer biology↗

bioRxiv2024

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

BACKGROUND & AIMSChronic 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 KrasG12D/+(Kras*) and CREB in promoting pancreatic cancer progression under chronic inflammation remains poorly understood. METHODSExperimental 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 (Crebfl/fl) in Ptf1aCreERTM/+;LSL-KrasG12D/+(KC) genetic mouse models (KCC-/-). Pancreata from Ptf1aCreERTM/+, 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. RESULTSACP 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. CONCLUSIONSOur 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.

cancer biology↗