Tumour extracellular vesicles and particles induce liver metabolic dysfunction

Gang Wang, Jianlong Li, Linda Bojmar, Haiyan Chen, Zhong Li, Gabriel C. Tobias, Mengying Hu, Edwin A. Homan, Serena Lucotti, Fengbo Zhao, Valentina Posada, Peter R. Oxley, Michele Cioffi, Han Sang Kim, Huajuan Wang, Pernille Lauritzen, Nancy Boudreau, Zhanjun Shi, Christin E. Burd, Jonathan H. Zippin, James C. Lo, Geoffrey S. Pitt, Jonathan Hernandez, Constantinos P. Zambirinis, Michael A. Hollingsworth, Paul M. Grandgenett, Maneesh Jain, Surinder K. Batra, Dominick J. DiMaio, Jean L. Grem, Kelsey A. Klute, Tanya M. Trippett, Mikala Egeblad, Doru Paul, Jacqueline Bromberg, David Kelsen, Vinagolu K. Rajasekhar, John H. Healey, Irina R. Matei, William R. Jarnagin, Robert E. Schwartz (), Haiying Zhang () and David Lyden ()
Additional contact information
Gang Wang: Weill Cornell Medicine
Jianlong Li: Weill Cornell Medicine
Linda Bojmar: Weill Cornell Medicine
Haiyan Chen: Weill Cornell Medicine
Zhong Li: Duke University School of Medicine
Gabriel C. Tobias: Weill Cornell Medicine
Mengying Hu: Weill Cornell Medicine
Edwin A. Homan: Weill Cornell Medicine
Serena Lucotti: Weill Cornell Medicine
Fengbo Zhao: Weill Cornell Medicine
Valentina Posada: The Ohio State University
Peter R. Oxley: Samuel J. Wood Library, Weill Cornell Medicine
Michele Cioffi: Weill Cornell Medicine
Han Sang Kim: Weill Cornell Medicine
Huajuan Wang: Weill Cornell Medicine
Pernille Lauritzen: Weill Cornell Medicine
Nancy Boudreau: Weill Cornell Medicine
Zhanjun Shi: Nanfang Hospital, Southern Medical University
Christin E. Burd: The Ohio State University
Jonathan H. Zippin: Weill Cornell Medical College of Cornell University
James C. Lo: Weill Cornell Medicine
Geoffrey S. Pitt: Weill Cornell Medicine
Jonathan Hernandez: Memorial Sloan Kettering Cancer Center
Constantinos P. Zambirinis: Memorial Sloan Kettering Cancer Center
Michael A. Hollingsworth: University of Nebraska Medical Center
Paul M. Grandgenett: University of Nebraska Medical Center
Maneesh Jain: University of Nebraska Medical Center
Surinder K. Batra: University of Nebraska Medical Center
Dominick J. DiMaio: University of Nebraska Medical Center
Jean L. Grem: University of Nebraska Medical Center
Kelsey A. Klute: University of Nebraska Medical Center
Tanya M. Trippett: Memorial Sloan Kettering Cancer Center
Mikala Egeblad: Cold Spring Harbor Laboratory
Doru Paul: Weill Cornell Medicine
Jacqueline Bromberg: Memorial Sloan Kettering Cancer Center
David Kelsen: Memorial Sloan Kettering Cancer Center
Vinagolu K. Rajasekhar: Memorial Sloan Kettering Cancer Center
John H. Healey: Memorial Sloan Kettering Cancer Center
Irina R. Matei: Weill Cornell Medicine
William R. Jarnagin: Memorial Sloan Kettering Cancer Center
Robert E. Schwartz: Weill Cornell Medicine
Haiying Zhang: Weill Cornell Medicine
David Lyden: Weill Cornell Medicine

Nature, 2023, vol. 618, issue 7964, 374-382

Abstract: Abstract Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs—particularly palmitic acid—induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

Date: 2023
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DOI: 10.1038/s41586-023-06114-4

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