Decreased NADPH production, which powers cellular processes, results in cancer progression

Tissue sample from a mouse without lesions (left) and with precancerous lesions due to loss of malic enzyme 1. Credit: Megan Radyk

Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer and has a low five-year survival rate. It begins with a reversible state called acinar-to-ductal metaplasia, where cells can heal after injury or inflammation. If there are cancer-causing mutations, metaplasia can continue progressing towards cancer.

In a new study published in Nature Metabolism, researchers identified cellular pathways that can influence metabolic changes when 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,” said Megan Radyk, Ph.D., a former Postdoctoral Fellow in the Lyssiotis lab and Assistant Professor at Roswell Park Comprehensive Cancer Center.

“We wanted to learn about what metabolic changes happen before you get an established tumor.”

In the current study, the researchers conducted RNA-sequencing to identify what cellular pathways are important for metaplasia and precancerous lesions in the pancreas. They found that two enzymes—glucose-6-phosphate dehydrogenase and malic enzyme 1—were present at higher levels. Using mouse models, the team found that decreased activity of glucose-6-phosphate dehydrogenase increased the number of precancerous lesions.

They found similar results in mouse models that did not have malic enzyme 1. Both enzymes make NADPH, a molecule that cells use to build lipids and nucleic acids like DNA and RNA. NADPH also helps cells lower the amount of lesion-forming reactive oxygen species. 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. The increased precancerous lesion formation could be prevented by treating the cells with the antioxidant glutathione or animals with the antioxidant N-acetyl cysteine.

The results were the same in pancreatic tissues from human donors. While both enzymes make NADPH, the researchers observed that loss of only malic enzyme 1 caused 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 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. They will also investigate whether patients who have mutations in either enzyme have an increased risk of 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.”

Source – Michigan Medicine