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Metabolite utilization profile 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, provides insight into both biochemical processes and potential therapeutic pathways.

The findings, published in Nature, show that cancer cells can adapt to the lack of access to glucose. Researchers have previously identified other substances that serve as fuel sources for pancreatic cancer; This study adds uridine to the catalog.

Because the pancreas has few functioning blood vessels, it cannot easily access nutrients such as glucose from the blood. Without the right nutrients, cancer cells proliferate, says Kostas Lissiotis, Ph.D., Messel Oncology Research Professor and lead investigator of the study. “We know they still grow, obviously, but what do they use to grow?” he said. “These findings show that, under certain conditions, uridine is one of these fuels.”

Asked about the effect, Zeribe Nwosu PhD, one of the first authors of the study, said: “I have long been fascinated by the ability of cancer to switch to alternative substances. Blocking such compensatory switches may lead us to new treatments and that is the door we hope this study opens.”

Uridine is found in the tumor microenvironment, but the exact source and how cancer cells reach it, remains a mystery. “Part of the picture is in the bloodstream, but we don’t know specifically where it’s coming from,” Lisiotis said. “Maybe, it’s coming from multiple places, and we haven’t been able to pin it down to one source yet.”

Events that Lisiotis calls “crisis periods”—when cells are starved of nutrients, limited blood supply, and/or intense competition between cells—will provide clues as to why and where cells convert to uridine. “Cancer cells seem to be sensitive to the local levels of glucose and uridine,” said Matt Ward, another first author. The Leisiots group identifies this unknown regulatory process and cancer-promoting mutations in the KRAS gene, common in pancreatic cancer, as two ways cancer cells use uridine.

Lisiotis and his team have been working on this research for almost a decade, along with collaborators in the Sadhanadam laboratory at the Institute of Cancer Research in London. They used technology that screened hundreds of different substances to determine which ones promoted the growth of pancreatic cancer. Typically, researchers look at standard nutrients like sugar, protein and fat, but Lisiotis’ team took an unbiased approach.

“We used a large panel of more than 20 pancreatic cell lines and nearly 200 different substances to evaluate the different ways in which pancreatic cancer cells grow,” he explained. “What do they actually metabolize? This method led us to find uridine.”

This method provides medical insight. The findings show that uridine is metabolized by the enzyme uridine phosphorylase-1 or UPP1. Blocking UPP1 had a significant effect on the growth of pancreatic tumors in mice, findings that point to the need to test uridine-inhibiting drugs as possible new therapeutic options.

“There is potential to better understand and treat pancreatic cancer with new drug targets and new therapies,” said Sadhanadam, co-author of the study.

More research is needed to determine the best way to transfer this finding to the clinic.

Additional information:
Zeribe C. Nwosu et al., Uridine-derived ribose in glucose-limited pancreatic cancer, Nature (2023) DOI: 10.1038/s41586-023-06073-w

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