MSGID: 1:317/3 6466fb6a   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Cancer cells use a new fuel in absence of sugar    
    A new study shows that, in mice, the metabolite uridine can feed   
   pancreatic cancer cells when glucose availability is low    
      
     Date:   
         May 18, 2023   
     Source:   
         Michigan Medicine - University of Michigan   
     Summary:   
         Researchers have discovered a new nutrient source that pancreatic   
         cancer cells use to grow. The molecule, uridine, offers insight into   
         both biochemical processes and possible therapeutic pathways. The   
         findings show that cancer cells can adapt when they don't have   
         access to glucose.   
      
      
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   FULL STORY   
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   Researchers at the University of Michigan Rogel Cancer Center have   
   discovered a new nutrient source 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 don't have access to glucose. Researchers have previously 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 can't easily   
   access nutrients that come from the bloodstream, like glucose. Costas   
   Lyssiotis, Ph.D., Maisel Research Professor of Oncology and lead   
   investigator of the study, explained that without the right nutrients,   
   the cancer cells get hungry.   
      
   "We know they still grow, obviously, but what are they using to grow?" he   
   said.   
      
   "These findings show that, under certain circumstances, uridine is one   
   of those fuels."  Asked about impact, Zeribe Nwosu, Ph.D., one of the   
   co-first authors in the study, says "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 treatments and that's 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 it's in the bloodstream, but we   
   don't know where it's coming from specifically," said Lyssiotis. "Likely,   
   it's 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, because of limited   
   blood access and/or intense competition between cells -- could be a clue   
   as to why, and where, cells turn to uridine.   
      
   "The cancer cells seem to be sensing the concentrations of glucose and   
   uridine in the local environment to inform their adaptation," says Matt   
   Ward, another co-first author. Lyssiotis' team recognize 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 their usage of uridine.   
      
   Lyssiotis and his team have been working on this research for nearly   
   a decade alongside their collaborators in the Sadanandam lab at the   
   Institute for Cancer Research in London. They used a technology that   
   screens hundreds of different nutrients to see which ones support   
   pancreatic cancer growth. 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 over 20 pancreatic cell   
   lines and around 200 different nutrients to assess different ways   
   pancreatic cancer cells grow," he explained. "What do they actually   
   metabolize? This method led us to discover uridine."  This method   
   offers therapeutic insight, too. The findings showed that uridine is   
   metabolized by the enzyme uridine phoshorylase-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's potential to better understand and treat pancreatic cancer   
   with new drug targets and new therapeutic approaches," said Sadanandam,   
   co-author on the study.   
      
   More research is needed to determine the best way to move this discovery   
   to the clinic.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Pancreatic_Cancer # Cancer # Brain_Tumor # Lung_Cancer   
             o Plants_&_Animals   
                   # Mice # Biology # Biotechnology # Genetics   
       * RELATED_TERMS   
             o Prostate_cancer o Metastasis o Immune_system o   
             Monoclonal_antibody_therapy o Cancer o Blood_sugar o   
             Cervical_cancer o Colorectal_cancer   
      
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   Story Source: Materials provided by   
   Michigan_Medicine_-_University_of_Michigan. Original written by Anna   
   Megdell. Note: Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Zeribe C. Nwosu, Matthew H. Ward, Peter Sajjakulnukit, Pawan Poudel,   
         Chanthirika Ragulan, Steven Kasperek, Megan Radyk, Damien Sutton,   
         Rosa E.   
      
         Menjivar, Anthony Andren, Juan J. Apiz-Saab, Zachary Tolstyka,   
         Kristee Brown, Ho-Joon Lee, Lindsey N. Dzierozynski, Xi He, Hari PS,   
         Julia Ugras, Gift Nyamundanda, Li Zhang, Christopher J. Halbrook,   
         Eileen S. Carpenter, Jiaqi Shi, Leah P. Shriver, Gary J. Patti,   
         Alexander Muir, Marina Pasca di Magliano, Anguraj Sadanandam,   
         Costas A. Lyssiotis. Uridine-derived ribose fuels glucose-restricted   
         pancreatic cancer. Nature, 2023; DOI: 10.1038/s41586-023-06073-w   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/05/230518120901.htm   
      
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