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. ZippinJames 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, David Lyden

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)374-382
Number of pages9
Issue number7964
StatePublished - Jun 8 2023

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Tumour extracellular vesicles and particles induce liver metabolic dysfunction'. Together they form a unique fingerprint.

Cite this