Tumour extracellular vesicles and particles induce liver metabolic dysfunction.

TitleTumour extracellular vesicles and particles induce liver metabolic dysfunction.
Publication TypeJournal Article
Year of Publication2023
AuthorsWang G, Li J, Bojmar L, Chen H, Li Z, Tobias GC, Hu M, Homan EA, Lucotti S, Zhao F, Posada V, Oxley PR, Cioffi M, Kim HSang, Wang H, Lauritzen P, Boudreau N, Shi Z, Burd CE, Zippin JH, Lo JC, Pitt GS, Hernandez J, Zambirinis CP, Hollingsworth MA, Grandgenett PM, Jain M, Batra SK, DiMaio DJ, Grem JL, Klute KA, Trippett TM, Egeblad M, Paul D, Bromberg J, Kelsen D, Rajasekhar VK, Healey JH, Matei IR, Jarnagin WR, Schwartz RE, Zhang H, Lyden D
Date Published2023 Jun
KeywordsAnimals, Cytochrome P-450 Enzyme System, Extracellular Vesicles, Fatty Acids, Fatty Liver, Humans, Inflammation, Kupffer Cells, Liver, Liver Neoplasms, Mice, Oxidative Phosphorylation, Palmitic Acid, Pancreatic Neoplasms, rab27 GTP-Binding Proteins, Tumor Microenvironment, Tumor Necrosis Factor-alpha

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.

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Alternate JournalNature
PubMed ID37225988
PubMed Central IDPMC10330936
Grant ListU54 CA163117 / CA / NCI NIH HHS / United States
R01 CA218513 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA254036 / CA / NCI NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
P30 CA016058 / CA / NCI NIH HHS / United States
R01 DK121072 / DK / NIDDK NIH HHS / United States
T32 HL160520 / HL / NHLBI NIH HHS / United States
R01 CA237213 / CA / NCI NIH HHS / United States
R01 AI107301 / AI / NIAID NIH HHS / United States
R35 CA232093 / CA / NCI NIH HHS / United States
R01 CA207983 / CA / NCI NIH HHS / United States
R01 CA234614 / CA / NCI NIH HHS / United States

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