Tumour extracellular vesicles and particles induce liver metabolic dysfunction

Wang, Gang, Li, Jianlong, Bojmar, Linda, Chen, Haiyan, Li, Zhong, Tobias, Gabriel C, Hu, Mengying, Homan, Edwin A, Lucotti, Serena, Zhao, Fengbo, Posada, Valentina, Oxley, Peter R, Cioffi, Michele, Kim, Han Sang, Wang, Huajuan, Lauritzen, Pernille, Boudreau, Nancy, Shi, Zhanjun, Burd, Christin E, Zippin, Jonathan H, Lo, James C, Pitt, Geoffrey S, Hernandez, Jonathan, Zambirinis, Constantinos P, Hollingsworth, Michael A, Grandgenett, Paul M, Jain, Maneesh, Batra, Surinder K, DiMaio, Dominick J, Grem, Jean L, Klute, Kelsey A, Trippett, Tanya M, Egeblad, Mikala, Paul, Doru, Bromberg, Jacqueline, Kelsen, David, Rajasekhar, Vinagolu K, Healey, John H, Matei, Irina R, Jarnagin, William R, Schwartz, Robert E, Zhang, Haiying, Lyden, David (June 2023) Tumour extracellular vesicles and particles induce liver metabolic dysfunction. Nature, 618 (7964). pp. 374-382. ISSN 0028-0836 (Public Dataset)

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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.

Item Type: Paper
Subjects: bioinformatics
diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > neoplasms
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
organism description > animal
diseases & disorders > inflammation
organs, tissues, organelles, cell types and functions > organs types and functions > liver
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
organs, tissues, organelles, cell types and functions > organs types and functions
organs, tissues, organelles, cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression > phosphorylation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression
organism description > animal > mammal > rodent
CSHL Authors:
Communities: CSHL labs > Egeblad lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: June 2023
Date Deposited: 22 Sep 2023 16:09
Last Modified: 11 Jan 2024 14:44
PMCID: PMC10330936
Related URLs:
Dataset ID:
URI: https://repository.cshl.edu/id/eprint/40981

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