A common sugar may help cancer cells break free and spread

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.