CREB Fuels Tumorigenesis in Alcoholic Pancreatitis

Alcoholic chronic pancreatitis (ACP) is a major risk factor for pancreatic ductal adenocarcinoma (PDAC), with long-term alcohol consumption being the primary cause of most chronic pancreatitis cases. Epidemiologic studies indicate that individuals with a history of heavy alcohol use have a 4-fold higher risk of developing pancreatitis compared with nondrinkers.¹ Emerging data additionally show moderate alcohol use is an independent risk factor for the development of pancreatic cancer, with studies showing a 3% risk for every additional 10 g of alcohol consumed daily.2, 3, 4 Recurrent alcohol-induced injury promotes persistent inflammation, acinar cell loss, and fibrosis, pathological hallmarks that create a pro-tumorigenic environment.^5,6 Yet, despite these well-documented clinical and pathological associations, the molecular mechanisms that link chronic inflammatory injury to oncogenic transformation remain poorly defined. In particular, how alcohol-mediated pancreatic injury interacts with genetic drivers such as mutant KRAS to initiate and sustain neoplastic transformation is not fully understood.

Addressing this critical gap, Srinivasan et al, in a previous issue of Cellular and Molecular Gastroenterology and Hepatology, identify cAMP response element-binding protein (CREB) as a pivotal mediator linking chronic pancreatic inflammation to tumorigenesis in the context of ACP (Figure 1).⁷ Using Ptf1aCreERTM/+ mice, the authors demonstrate that ACP triggers profound pancreatic remodeling, including expansion of ductal-like cells with elevated phosphorylated CREB (pCREB) expression, suppression of acinar identity genes, activation of pancreatic stellate cells, collagen deposition, and infiltration of CD45+ immune cells. Remarkably, these injury-associated changes reversed after a 21-day recovery period: pCREB levels declined, and acinar-to-ductal metaplasia (ADM) structures redifferentiated to restore acinar morphology, demonstrating the intrinsic regenerative capacity of the pancreas once the injurious stimulus is removed.

Figure 1.

Chronic alcohol-induced pancreatic injury activates CREB signaling and accelerates KRAS-driven neoplastic transformation. Recurrent alcohol exposure induces chronic pancreatic inflammation, acinar cell loss, and fibrosis, creating a pro-tumorigenic microenvironment. In this setting, CREB activation promotes ADM, ductal cell expansion, and immune cell infiltration. In mice harboring oncogenic KRAS (KC), ACP dramatically accelerates PanIN progression and shortens tumor latency, with sustained CREB activation observed in ductal-like structures. CREB ablation in acinar cells (KCC mice) suppresses ADM, reduces tumor-associated stromal responses, and significantly delays PDAC development, highlighting CREB as a key link between environmental injury, inflammation, and oncogenic transformation.

To interrogate the oncogenic consequences of ACP, the authors employed the Ptf1aCreERTM/+; LSL-KrasG12D/+ (KC) model of oncogenic KRAS-driven pancreatic cancer. Strikingly, ACP exposure in KC mice led to accelerated neoplastic progression. Compared with control KC animals, ACP-induced KC mice developed high-grade pancreatic intraepithelial neoplasia (PanIN), showed loss of acinar cells, pronounced desmoplasia with activated pancreatic stellate cells, dense infiltration of CD45+ immune cells, and elevated pCREB expression. Tumor latency was shortened from 9.76 months in controls to just 5.8 months in ACP-exposed KC mice. Notably, pCREB remained elevated even during recovery and localized to CK19⁺ ductal structures, many of which, via lineage tracing, were shown to originate from acinar cells. These findings implicate CREB as a key driver of acinar reprogramming and early neoplastic transformation in the setting of ACP and mutant KRAS.

To test the functional importance of CREB, the authors generated Ptf1aCreERTM/+; LSL-KrasG12D/+; Crebfl/fl, (KCC) mice with acinar-specific CREB deletion. Strikingly, KCC mice developed only low-grade PanIN lesions, in contrast to the high-grade PanINs and invasive cancers observed in KC mice within 10 months. Ductal gene expression was markedly reduced in KCC mice, demonstrating that CREB ablation blunts ADM reprogramming. Moreover, when ACP was induced in KCC animals, CREB deletion limited ductal expansion, mucin accumulation, desmoplasia, and immune cell infiltration, while preserving a higher proportion of acinar (amylase-positive) cells. CREB loss significantly prolonged tumor latency from 5.8 months in ACP-induced KC mice to 14.8 in ACP-induced KCC mice, highlighting CREB’s potential as a therapeutic target to delay pancreatic cancer progression in the setting of chronic pancreatitis. These results strongly suggest that CREB is necessary for KRAS-driven neoplastic progression, especially in the setting of chronic inflammatory injury.

Beyond its role in acinar plasticity, Srinivasan et al provide compelling evidence that CREB acts as a master regulator of pancreatic cancer progression. Activated by oncogenic KRAS through the MAPK/MEK and PI3K/AKT signaling axes, CREB drives transcriptional programs that promote tumor initiation and progression. Previous studies have shown that activated CREB interacts with mutant p53 to induce pro-metastatic transcriptional programs involving FOXA1 and the Wnt/β-catenin axis, illustrating how mutant KRAS and mutant p53 converge on CREB to amplify oncogenic signaling and drive pancreatic cancer aggressiveness. Inhibition of CREB phosphorylation or disruption of the CREB-p53 interaction markedly reduces PDAC metastasis in vivo, underscoring the therapeutic potential of targeting this signaling node.⁸ Moreover, crosstalk between CREB and β-catenin-associated coactivators such as CBP further amplify oncogenic transcriptional output, and pharmacologic disruption of the CREB-CBP complex has been shown to reduce tumor burden in preclinical PDAC models.⁹

Together, these findings place CREB as a critical nexus linking environmental injury, inflammation, acinar cell plasticity, and oncogenic KRAS signaling, suggesting that CREB acts not only as a downstream effector of oncogenic pathways but also as a mediator of environmental stress responses that prime the pancreas for malignancy. The reversibility of ADM in the absence of CREB and the striking delay in tumor latency with CREB ablation underscores its therapeutic promise. Collectively, this work advances our understanding of how inflammation, oncogenic signaling, and environmental injury converge in PDAC and highlights CREB inhibition as a promising strategy to mitigate cancer risk in high-risk settings such as alcoholic pancreatitis.