Researchers at the University of Michigan’s Rogel Cancer Center have discovered a new source of nutrients that pancreatic cancer cells use to grow. The uridine molecule provides insight into both biochemical processes and possible therapeutic pathways.
Results published in natureIt turns out that cancer cells can adapt when they don’t have access to glucose. Researchers have previously identified other nutrients that act 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. Without the right nutrients, cancer cells become hungry, explained Kostas Lisiotis, PhD, Maisel Research Professor of Oncology and the study’s principal investigator. “We know they’re still growing, of course, but what are they using to grow?” He said. “These results show that, under certain conditions, uridine is one of those fuels.”
When asked about the effect, Zirabe Nwoso, PhD, one of the study’s co-authors, said, “The ability of cancer to switch to alternative nutrients has fascinated me for a long time. Blocking such compensatory switches could lead us to new therapies and that’s the door.” Which we hope this study will open up.”
Uridine is present in the tumor microenvironment, but its exact source, and how cancer cells access it, remains a mystery. “Part of the picture is in the bloodstream, but we don’t know where it came from specifically,” Lysiotis said. “It’s likely coming from multiple places, and so far we haven’t been able to pin it to a single source.”
Events that Lyssiotis refers to as “times of crisis”—when cells don’t have enough nutrients, due to limited access to blood and/or intense competition between cells—could be a clue as to why and where the cells’ uridine is headed. “It appears that cancer cells sense glucose and uridine concentrations in the local environment to inform their adaptation,” says Matt Ward, another co-first author. Lyssiotis’ team identifies this little-known regulatory process, along with a cancer-promoting mutation in the KRAS gene, which is common in pancreatic cancer, as two ways in which cancer cells control the use of uridine.
Lyssiotis and his team have been working on this research for nearly a decade, along with their collaborators in Sadanandam’s lab at the Institute of Cancer Research in London. They used a technique that screens hundreds of different nutrients to see which ones support the growth of pancreatic cancer. Typically, researchers look at standard nutrients like sugar, protein, and fat, but Lysciotis’ team took an unbiased approach. “We used a large panel of more than 20 pancreatic cell lineages and about 200 different nutrients to assess the different ways in which pancreatic cancer cells grow,” he explained. “What is actually metabolized? This method led us to the discovery of uridine.”
This method provides a therapeutic outlook as well. The results show that uridine is metabolized by the enzyme uridine photophorylase-1, or UPP1. Blocking UPP1 had a significant effect on the growth of pancreatic tumors in mice, findings which indicate the importance of testing uridine-blocking drugs as potential new therapeutic options.
“There is potential to better understand and treat pancreatic cancer through novel drug targets and novel therapeutic approaches,” said Sadanandam, co-author of the study.
More research is needed to determine the best way to bring this finding to the clinic.