Study finds cancer cells use new fuel in the absence of sugar

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Profiling of metabolite utilization in PDA cells identifies uridine. Credit: Nature (2023). DOI: 10.1038/s41586-023-06073-w

Researchers at the University of Michigan Rogel Cancer Center have discovered a new source of nutrients that pancreatic cancer cells use to grow. The molecule, uridine, offers insight into both biochemical processes and possible therapeutic pathways.

The findings, published in Nature, show that cancer cells can adapt when they do not have access to glucose. Researchers have already identified other nutrients that serve as fuel sources for pancreatic cancer; this study adds uridine to the catalog.

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

Asked about the impact, Zeribe Nwosu, Ph.D., one of the study’s co-first authors, said, “The ability of cancer to switch to alternative nutrients has fascinated me for a long time. Blocking such Compensatory changes could lead us to new treatments and this is the door we hope this study will open.”

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 that it’s in the bloodstream, but we don’t know where it came from specifically,” Lyssiotis said. “It’s probably coming from multiple places, and so far we haven’t been able to pin it to one source.”

The events that Lyssiotis calls “crisis periods” – 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 cells turn to uridine. “Cancer cells appear to sense glucose and uridine concentrations in the local environment to inform their adaptation,” says Matt Ward, another co-first author. The Lyssiotis team recognizes this unknown 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 their use of uridine.

Lyssiotis and his team have been working on this research for almost a decade alongside their collaborators in the Sadanandam laboratory at the Institute for Cancer Research in London. They used technology that filters hundreds of different nutrients to see which promote the growth of pancreatic cancer. Typically, researchers look at standard nutrients like sugar, protein, and fat, but the Lyssiotis team took an unbiased approach.

“We used a large panel with over 20 pancreatic cell lines and about 200 different nutrients to assess the different ways pancreatic cancer cells grow,” he explained. “What do they actually metabolize? This method led us to discover uridine.”

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

“There is potential to better understand and treat pancreatic cancer with new drug targets and therapeutic approaches,” said study co-author Sadanandam.

Further research is needed to determine how best to transfer this finding to the clinic.

More information:
Zeribe C. Nwosu et al, uridine-derived ribose fuels glucose-restricted pancreatic cancer, Nature (2023). DOI: 10.1038/s41586-023-06073-w

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