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 ========================================================================== 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

========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Anna
Megdell. Note: Content may be edited for style and length.


========================================================================== 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/05/230518120901.htm

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