Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer

Ronald Fowle-Grider, Joe L. Rowles, Isabel Shen, Yahui Wang, Michaela Schwaiger-Haber, Alden J. Dunham, Kay Jayachandran, Matthew Inkman, Michael Zahner, Fuad J. Naser, Madelyn M. Jackstadt, Jonathan L. Spalding, Sarah Chiang, Kyle S. McCommis, Roland E. Dolle, Eva T. Kramer, Sarah M. Zimmerman, George P. Souroullas, Brian N. Finck, Leah P. Shriver, Charles K. Kaufman, Julie K. Schwarz, Jin Zhang and Gary J. Patti ()
Additional contact information
Ronald Fowle-Grider: Washington University
Joe L. Rowles: Washington University
Isabel Shen: Washington University
Yahui Wang: Washington University
Michaela Schwaiger-Haber: Washington University
Alden J. Dunham: Washington University
Kay Jayachandran: Washington University School of Medicine
Matthew Inkman: Washington University School of Medicine
Michael Zahner: Washington University School of Medicine
Fuad J. Naser: Washington University
Madelyn M. Jackstadt: Washington University
Jonathan L. Spalding: Washington University
Sarah Chiang: Washington University
Kyle S. McCommis: Saint Louis University School of Medicine
Roland E. Dolle: Washington University School of Medicine
Eva T. Kramer: Washington University School of Medicine
Sarah M. Zimmerman: Washington University School of Medicine
George P. Souroullas: Washington University School of Medicine
Brian N. Finck: Washington University School of Medicine
Leah P. Shriver: Washington University
Charles K. Kaufman: Washington University School of Medicine
Julie K. Schwarz: Washington University School of Medicine
Jin Zhang: Washington University School of Medicine
Gary J. Patti: Washington University

Nature, 2024, vol. 636, issue 8043, 737-744

Abstract: Abstract Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener1. It has been proposed that fructose promotes the growth of some tumours directly by serving as a fuel2,3. Here we show that fructose supplementation enhances tumour growth in animal models of melanoma, breast cancer and cervical cancer without causing weight gain or insulin resistance. The cancer cells themselves were unable to use fructose readily as a nutrient because they did not express ketohexokinase-C (KHK-C). Primary hepatocytes did express KHK-C, resulting in fructolysis and the excretion of a variety of lipid species, including lysophosphatidylcholines (LPCs). In co-culture experiments, hepatocyte-derived LPCs were consumed by cancer cells and used to generate phosphatidylcholines, the major phospholipid of cell membranes. In vivo, supplementation with high-fructose corn syrup increased several LPC species by more than sevenfold in the serum. Administration of LPCs to mice was sufficient to increase tumour growth. Pharmacological inhibition of ketohexokinase had no direct effect on cancer cells, but it decreased circulating LPC levels and prevented fructose-mediated tumour growth in vivo. These findings reveal that fructose supplementation increases circulating nutrients such as LPCs, which can enhance tumour growth through a cell non-autonomous mechanism.

Date: 2024
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DOI: 10.1038/s41586-024-08258-3

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