A new study shows that, in mice, the metabolite uridine can feed pancreatic cancer cells when glucose availability is low

Featured Sponsor

Store	Link	Sample Product
UK Artful Impressions	Premiere Etsy Store

The findings, published in Nature, show that cancer cells can adapt when they don’t have access to glucose. Researchers previously identified other nutrients that serve as fuel sources for pancreatic cancer; this study adds uridine to the catalogue.

Pancreatic tumors have few functioning blood vessels and cannot easily access nutrients that come from the bloodstream, such as glucose. Costas Lyssiotis, Ph.D., Maisel Research Professor of Oncology and the study’s principal investigator, explained that without adequate nutrients, cancer cells starve. “We know they’re still growing, obviously, but what are they using to grow?” he said. “These findings show that, under certain circumstances, uridine is one of those fuels.”

When asked about the impact, Zribe Nwosu, Ph.D., one of the study’s first co-authors, says that “cancer’s ability to switch to alternative nutrients has long fascinated me. Blocking such compensatory changes could lead us to new treatments, and that’s the door we hope this study will open.”

Uridine is present in the tumor microenvironment, but its exact origin and how cancer cells access it remain a mystery. “Part of the picture is that it’s in the bloodstream, but we don’t know where it’s coming from specifically,” Lyssiotis said. “It probably comes from several places, and so far we have not been able to identify it in a single source.”

The events that Lyssiotis refers to as “crisis times” (when cells do not have enough nutrients, due to limited access to blood and/or intense competition between cells) could be a clue as to why and where. cells recur. uridine. “Cancer cells appear to be sensing glucose and uridine concentrations in the local environment to inform their adaptation,” says Matt Ward, another co-author. Lyssiotis’s team recognizes this unknown regulatory process, as well as a cancer-promoting mutation in the KRAS gene, which is common in pancreatic cancer, as two ways that cancer cells control uridine use.

Lyssiotis and his team have been working on this research for almost a decade together with their collaborators in Sadanandam’s lab at the Institute for Cancer Research in London. They used technology that analyzes hundreds of different nutrients to see which ones promote the growth of pancreatic cancer. Typically, researchers look at standard nutrients like sugar, protein and fat, but Lyssiotis’s team took an unbiased approach. “We used a large panel with more than 20 pancreatic cell lines and about 200 different nutrients to test the different ways pancreatic cancer cells grow,” she explained. “What do they actually metabolize? This method led us to discover uridine.”

This method also offers therapeutic information. The findings showed that uridine is metabolized by the enzyme uridine phosphorylase-1, or UPP1. UPP1 blockade had a major impact on the growth of pancreatic tumors in mice, findings that suggest the importance of testing uridine-blocking drugs as potential new treatment options.

“The potential exists to better understand and treat pancreatic cancer with new drug targets and new therapeutic approaches,” said Sadanadam, co-author of the study.

More research is needed to determine the best way to translate this discovery into the clinic.