Researchers reported on Apr. 3 that specific metabolic pathways play a role in the progression from pancreatic lesions to cancer, according to a new study published in Nature Metabolism.
Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer and has a low five-year survival rate. The disease often begins with acinar-to-ductal metaplasia, a reversible condition where cells can heal after injury or inflammation. However, if there are cancer-causing mutations present, this state can continue progressing towards cancer.
The study used RNA-sequencing to identify cellular pathways important for metaplasia and precancerous lesions in the pancreas. Researchers found that two enzymes—glucose-6-phosphate dehydrogenase and malic enzyme 1—were present at higher levels during these stages. In mouse models, decreased activity of glucose-6-phosphate dehydrogenase led to an increase in precancerous lesions, as did the absence of malic enzyme 1.
Both enzymes produce NADPH, which cells use to build lipids and nucleic acids such as DNA and RNA. NADPH also helps reduce lesion-forming reactive oxygen species within cells. When levels of these enzymes were lower, researchers observed higher amounts of reactive oxygen species and increased formation of precancerous lesions. Treating cells with antioxidants like glutathione or animals with N-acetyl cysteine prevented this increase in lesion formation; similar results were seen in human pancreatic tissue samples.
Importantly, while both enzymes generate NADPH, only loss of malic enzyme 1 was linked directly to progression into cancer. "This difference highlights why it's important to understand what metabolic pathways are important during each stage of cancer progression," Radyk said.
The research team plans further studies on other enzymes that may influence NADPH production and will investigate whether patients with mutations in either enzyme have an increased risk for pancreatic disease. "Our study can help the search for new biomarkers that can intercept pancreatic cancer before it progresses," said Costas Lyssiotis, Ph.D., Professor of Molecular and Integrative Physiology and Co-Director of the Rogel and Blondy Center for Pancreatic Cancer. "Depending on the level of these enzymes, we could also identify a patient's risk for developing cancer."
