Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer and has a low five-year survival rate.<\/p>\n
It begins with a reversible state called acinar-to-ductal metaplasia, where cells can heal after injury or inflammation<\/a>.<\/p>\n If there are cancer-causing mutations, metaplasia can continue progressing towards cancer.<\/p>\n In a new study published in\u00a0Nature Metabolism,\u00a0researchers identified cellular pathways that can influence metabolic changes when cells progress from metaplasia to cancer.<\/p>\n Their results could help researchers treat benign lesions before they become tumors.<\/p>\n “We know a lot about how pancreatic tumors behave and look, but we don’t know how they become cancerous,” said Megan Radyk, Ph.D., a former Postdoctoral Fellow in the Lyssiotis lab and Assistant Professor at Roswell Park Comprehensive Cancer Center.<\/p>\n “We wanted to learn about what metabolic changes happen before you get an established tumor.”<\/p>\n In the current study, the researchers conducted RNA-sequencing to identify what cellular pathways are important for metaplasia and precancerous lesions in the pancreas.<\/p>\n They found that two enzymes-glucose-6-phosphate dehydrogenase and malic enzyme 1-were present at higher levels.<\/p>\n Using mouse models, the team found that decreased activity of glucose-6-phosphate dehydrogenase increased the number of precancerous lesions.<\/p>\n They found similar results in mouse models that did not have malic enzyme 1.<\/p>\n Both enzymes make NADPH, a molecule that cells use to build lipids and nucleic acids like DNA and RNA.<\/p>\n NADPH also helps cells lower the amount of lesion-forming reactive oxygen species.<\/p>\n The researchers found that when pancreatic cells have lower levels of glucose-6-phosphate dehydrogenase and malic enzyme 1, their levels of reactive oxygen species were higher.<\/p>\n The increased precancerous lesion formation could be prevented by treating the cells with the antioxidant glutathione or animals with the antioxidant N-acetyl cysteine.<\/p>\n The results were the same in pancreatic tissues from human donors.<\/p>\n While both enzymes make NADPH, the researchers observed that loss of only malic enzyme 1 caused progression into cancer.<\/p>\n “This difference highlights why it’s important to understand what metabolic pathways are important during each stage of cancer progression,” Radyk said.<\/p>\n The researchers are interested in identifying other enzymes that might influence the amount of NADPH in the cell, as well as druggable metabolic pathways that enable disease transformation.<\/p>\n They will also investigate whether patients who have mutations in either enzyme have an increased risk of pancreatic disease.<\/p>\n “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.<\/p>\n “Depending on the level of these enzymes, we could also identify a patient’s risk for developing cancer.”<\/p>\n Source:<\/p>\n Michigan Medicine – University of Michigan<\/a><\/p>\n Journal reference:<\/p>\n