Blocking CREB May Prevent Alcohol-Related Pancreatic Cancer
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Pancreatic cancer remains one of the most aggressive and difficult-to-treat cancers, with limited effective therapies. emerging research increasingly points to the significant role of chronic inflammation, particularly that induced by excessive alcohol consumption, in driving its development. A new study from the University of Miami Miller School of Medicine has pinpointed the CREB gene as a critical molecular orchestrator in this process, offering a potential new therapeutic target.
Alcohol,Inflammation,and the Path to Pancreatic Cancer
Excessive alcohol use is a recognized risk factor for pancreatic cancer,and is now considered the third leading preventable cause of cancer overall by the U.S. Surgeon General.The link isn’t direct; rather, alcohol triggers chronic inflammation of the pancreas – a condition known as alcoholic pancreatitis – which over time can lead to precancerous changes and ultimately, cancer.Researchers have long understood this connection,but the precise molecular mechanisms driving the conversion of healthy pancreatic cells into cancerous ones remained unclear. The new study sheds light on this process, focusing on acinar cells – the cells responsible for producing digestive enzymes in the pancreas.These cells are particularly vulnerable to alcohol-induced damage and inflammation.
How CREB Fuels Cancer Progression
The study, published in Cellular and Molecular Gastroenterology and hepatology, utilized a novel preclinical model that accurately replicates the stages of alcohol-induced pancreatic cancer development. This model incorporated cells with a common pro-cancerous Ras mutation, frequently found in pancreatic tumors, and allowed researchers to manipulate the CREB gene.
The research team found that exposure to alcohol and a pro-inflammatory molecule initiated a cascade of events mirroring alcoholic pancreatitis. This inflammation activated CREB,a gene known to play a role in various cellular processes,including inflammation and memory formation. Though, the study revealed CREB’s far more sinister role in pancreatic cancer: it doesn’t just mediate inflammation, it actively drives the conversion of healthy acinar cells into precancerous cells, ultimately leading to high-grade neoplasia – a hallmark of aggressive cancer.
“We found that CREB is not just a mediator of inflammation; it is a molecular orchestrator that permanently converts acinar cells into precancerous cells, which ultimately progress to high-grade neoplasia,” explains Dr.Nagaraj Nagathihalli, senior author of the study and associate professor of surgery at the University of Miami.
Crucially, when the researchers genetically “knocked out” the CREB gene in the model, they observed a dramatic reduction in the development of both precancerous lesions and full-blown cancer, even with continued alcohol exposure. CREB knockout also protected acinar cells from alcohol-induced damage. This demonstrates a causal link between CREB activation and cancer progression.
Therapeutic Implications: Targeting CREB for Prevention and Treatment
These findings open up exciting new avenues for preventing and treating alcohol-related pancreatic cancer. Inhibiting CREB activity could perhaps protect the pancreas from alcohol-induced damage and halt the progression of precancerous cells.”We believe this study lays the groundwork for future translational efforts targeting CREB as a therapeutic vulnerability in inflammation-associated pancreatic cancer,” says Dr. Nipun Merchant, study co-author and chief of surgical oncology at Sylvester Comprehensive Cancer Center.
Researchers are now actively investigating the potential of CREB inhibitors, some of which are already under development as cancer therapeutics, to specifically target this pathway. Further research is needed to determine if similar mechanisms are at play in human cells and tissues, and to identify other molecules and cells involved in the process. Dr. Nagathihalli also speculates that CREB activation may contribute to other alcohol-linked cancers beyond pancreatic cancer.
This research provides a significant step forward in understanding the complex interplay between alcohol, inflammation, and pancreatic cancer, offering a promising new target for intervention and potentially improving outcomes for individuals at risk.
source:
university of Miami miller School of Medicine. https://med.miami.edu/
Journal reference:
Srinivasan, S.,et al. (2025). CREB drives acinar to ductal cells reprogramming and promotes pancreatic cancer progression in preclinical models of alcoholic pancreatitis. Cellular and Molecular Gastroenterology and Hepatology. https://doi.org/10.1016/j.jcmgh.2025.101606