Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer and has a poor 5-year survival rate.
It begins with a reversible condition called acinar-to-ductal metaplasia, in which cells can heal after injury or inflammation.
If a cancer-causing mutation is present, metaplasia can continue to progress toward cancer.
In a new study published in natural metabolism, Researchers have identified cellular pathways that may influence metabolic changes as cells progress from metaplasia to cancer.
Their results could help researchers treat benign lesions before they become tumors.
“We know a lot about how pancreatic tumors behave and look, but we don’t know how they become cancerous,” says Megan Radik, Ph.D., a former postdoctoral fellow in the Lysiotis lab and assistant professor at Roswell Park Comprehensive Cancer Center.
“We wanted to know what metabolic changes occur before a tumor becomes established.”
In the current study, the researchers performed RNA sequencing to identify which cellular pathways are important for pancreatic metaplasia and precancerous lesions.
They found that two enzymes, glucose-6-phosphate dehydrogenase and malic enzyme 1, were present at high levels.
Using a mouse model, the research team found that decreased activity of glucose-6-phosphate dehydrogenase increased the number of precancerous lesions.
They found similar results in a mouse model lacking malic enzyme 1.
Both enzymes produce NADPH, a molecule that cells use to build lipids and nucleic acids such as DNA and RNA.
NADPH also helps cells reduce the amount of reactive oxygen species that form lesions.
The researchers found that lower levels of glucose-6-phosphate dehydrogenase and malate enzyme 1 in pancreatic cells were associated with higher levels of reactive oxygen species.
Increased formation of precancerous lesions may be prevented by treating cells with the antioxidant glutathione or treating animals with the antioxidant N-acetylcysteine.
The results were the same with pancreatic tissue from human donors.
Although both enzymes produce NADPH, the researchers observed that loss of only malate enzyme 1 caused progression to cancer.
“This difference highlights why it is important to understand which metabolic pathways are important at each stage of cancer progression,” Radik said.
Researchers are interested in identifying other enzymes that may influence the amount of NADPH in cells, as well as druggable metabolic pathways that may enable changes in the disease.
The team will also investigate whether patients with mutations in any of the enzymes have an increased risk of pancreatic disease.
“Our research may help in the search for new biomarkers that can stop pancreatic cancer before it progresses,” said Kostas Lysiotis, Ph.D., professor of molecular and integrative physiology and co-director of the Rogel and Blondie Pancreatic Cancer Center.
“Depending on the levels of these enzymes, we can also determine a patient’s risk of developing cancer.”
sauce:
Michigan Medicine – University of Michigan
Reference magazines:
DOI: 10.1038/s42255-026-01496-x
