A common sugar may help cancer cells break free and spread
The Wistar Institute
The researchers found that fructose serves as one of the
chemical messages released by these treatment-surviving cells. The discovery
reveals a previously unknown way that cancer cells left behind after therapy
may contribute to metastasis.
"Some cancer cells that survive chemotherapy aren't
dividing anymore, but they're still biologically active," said Aidan Cole,
Ph.D., a postdoctoral fellow in the lab of Katherine Aird, Ph.D., at The Wistar
Institute and first author on the study. "Instead, they continue to
release molecules that send signals to nearby cells. Our study is among the
first to show that a nutrient -- in this case, fructose -- can act as one of
those signals."
Why Ovarian Cancer Often Returns
Nearly all ovarian cancer patients receive platinum-based
chemotherapy, and the initial response is often strong. Even so, the cancer
returns in most cases and typically spreads throughout the abdominal cavity.
This process, known as metastasis, is responsible for roughly 90% of deaths
from the disease.
Previous studies have indicated that cancer cells surviving
chemotherapy may help drive recurrence by releasing a complicated mixture of
signaling molecules. To investigate this possibility, Cole and his colleagues
developed an experiment that separated the surviving cells from the substances
they released.
The team collected molecules produced by
chemotherapy-surviving cells and exposed other cancer cells to them. Those
released substances alone were enough to significantly increase the cancer
cells' ability to spread.
"As far as we know, this is the first time anyone has
shown, in a preclinical model rather than just a dish, that it's the molecules
these cells release -- not the cells themselves -- that drive the cancer's
spread," said Cole.
Fructose Acts as a Signal for Cancer Spread
The researchers then set out to determine which released
substance was causing this effect. Their analysis showed that the surviving
cancer cells produced fructose and used it as a signal that encouraged
neighboring cells to spread.
The team also found that high amounts of dietary fructose,
comparable to the levels present in sugary drinks, could encourage cancer
spread even when chemotherapy had not been given. This result raises the
possibility that dietary habits may influence how cancer progresses.
That possibility is especially notable because fructose is
widely consumed in the United States. In some people, high fructose corn syrup
accounts for ~8-20% of daily calorie intake. Unlike many risk factors that
patients cannot change, fructose intake can be reduced through dietary choices.
Researchers have not yet tested whether lowering fructose
consumption improves outcomes in patients. Still, the findings suggest that
nutrition may affect cancer progression in ways that were previously
overlooked.
How Fructose Helps Cancer Cells Escape
The team next investigated how fructose makes cancer cells
more likely to spread. Using several large-scale analytical methods, including
a CRISPR screen, they discovered that fructose lowers cholesterol production
inside neighboring cancer cells.
Cholesterol helps cells remain attached to one another,
functioning like a form of biological glue. When cholesterol levels fall, those
cellular bonds weaken, allowing cancer cells to separate more easily and move
into other areas.
This mechanism offers a possible explanation for how a
common nutrient can alter the physical behavior of tumor cells and increase
their ability to escape.
Questions About Statins and Chemotherapy
The discovery that reduced cholesterol production may
encourage cancer spread also has potential clinical significance. Statins,
which are used by 39 million people in the United States, work by lowering
cholesterol production.
In the study, statins alone weakened the connections between
cancer cells and made it easier for them to escape. The researchers are now
investigating whether these drugs could interfere with the effects of
chemotherapy.
However, the team emphasizes that the findings are not a
reason for patients to stop taking statins or any other prescribed medication.
"We haven't tested this effect in patients yet, but it
raises questions about combining cholesterol-lowering drugs with chemotherapy,
especially since ovarian cancer is most common in postmenopausal women who are
often already on statins," said Katherine Aird, Ph.D., professor and
co-leader of the Molecular and Cellular Oncogenesis Program in the Ellen and
Ronald Caplan Cancer Center at The Wistar Institute, and senior author of the
study.
The Mechanism May Affect Other Cancers
The researchers are also studying whether the same
fructose-related pathway could play a role in cancers beyond ovarian cancer.
"We think other cancers that spread within the torso --
pancreatic, colon, liver -- could behave similarly. We can't call it universal
yet, but we think the effects are not just limited to ovarian cancer,"
said Aird.
Aird and Cole have already begun planning follow-up studies
to determine whether the results can be reproduced in several other types of
cancer.
Co-authors: Raquel Buj, Apoorva Uboveja, Alexander Tom,
Amandine Amalric, Baixue Yang, Miho Naruse, Frederick Keeney, Andrew Kossenkov,
and Qin Liu from The Wistar Institute; Evan Levasseur, Hui Wang, Katarzyna M.
Kedziora, Naveen Kumar Tangudu, Jeff Danielson, Callen T. Wallace, Esther
Elishaev, Lauren Borho, Huda Atiya, Lan G. Coffman, Steffi Oesterreich, Aditi
U. Gurkar, Francesmary Modugno, and Simon C. Watkins from University of
Pittsburgh School of Medicine; Amal Elhaw, Sierra White, Danyang Li, Dorota E.
Jazwinska, Matthew S. Laird, George Tseng, Francisco J. Schopfer, Ioannis K.
Zervantonakis, Wayne Stallaert, and Nadine Hempel from University of
Pittsburgh; Adam Chatoff, Andrea Andress Huacachino, Mariola M. Marcinkiewicz,
and Nathaniel W. Snyder from Lewis Katz School of Medicine at Temple
University; Felicia Lazure and Ana P. Gomes from H. Lee Moffitt Cancer Center
& Research Institute; Hope A. Townsend, Robin D. Dowell, and Aaron Clauset
from University of Colorado Boulder; Denarda Dangaj from Ludwig Institute for
Cancer Research, University of Lausanne (UNIL); and Benjamin G. Bitler from
University of Colorado Anschutz Medical Campus.
Work supported by: National Institutes of Health grants R37
CA240625, R01 CA259111, R01 CA298386, P50 CA272218, T32 GM133332, R01 CA242021,
R21 CA267050, R21 CA291905, and U01 AG077923; American Cancer Society grant
RSG-19-113-01-CCG; Ovarian Cancer Research Alliance grant MIG-2023-2-1018;
Congressionally Directed Medical Research Program grants HT9425-23-1-0436,
W81XWH2110338, OC210139, and OC230324; HERA Ovarian Cancer Foundation; Melanoma
Research Foundation; Janet Burroughs Ovarian Cancer Foundation; Silicon Valley
Community Foundation Chan Zuckerberg Initiative DAF grant 2023-329680; UPMC
Hillman Cancer Center; and The Wistar Institute.
Journal Reference:
- Aidan
R. Cole, Raquel Buj, Apoorva Uboveja, Evan Levasseur, Alexander Tom, Hui
Wang, Katarzyna M. Kedziora, Adam Chatoff, Andrea Andress Huacachino,
Mariola M. Marcinkiewicz, Amandine Amalric, Baixue Yang, Naveen Kumar
Tangudu, Emily Noonan, Jeff Danielson, Miho Naruse, Amal Taher Elhaw,
Sierra White, Danyang Li, Callen T. Wallace, Frederick Keeney, Felicia
Lazure, Esther Elishaev, Lauren Borho, Hope A. Townsend, Robin D. Dowell,
Aaron Clauset, Dorota E. Jazwinska, Matthew S. Laird, Huda Atiya, Denarda Dangaj,
Lan G. Coffman, George Tseng, Steffi Oesterreich, Andrew Kossenkov, Qin
Liu, Ana P. Gomes, Aditi U. Gurkar, Francisco J. Schopfer, Francesmary
Modugno, Simon C. Watkins, Ioannis K. Zervantonakis, Benjamin G. Bitler,
Wayne Stallaert, Nadine Hempel, Nathaniel W. Snyder, Katherine M. Aird. The
chemotherapy-induced senescence-associated secretome promotes cell
detachment and metastatic dissemination through metabolic reprogramming. Nature
Aging, 2026; DOI: 10.1038/s43587-026-01172-5
