Extracellular vesicles and particles derived from tumors with extrahepatic metastatic tropism induce liver dysregulation. Extracellular vesicles and particles derived from tumors with extrahepatic metastatic tropism induce liver dysregulation

Cancer is a systemic disease that includes several noted features, such as pre-metastatic niche formation, cachexia, and immune dysregulation. However, the mechanisms underlying multi-organ failure remain to be further investigated. Here, we show that inflammation, fatty liver, and dysregulated metabolism are hallmarks of systemically affected livers in various animal tumor models and cancer patients in the absence of hepatic metastasis. We identify that tumor-derived extracellular vesicles and particles (EVPs) are crucial mediators of cancer-induced hepatic functional reprogramming. Tumor EVPs package multiple fatty acids, such as palmitic acid, and target Kupffer cells upregulating tumor necrosis factor alpha (TNFα) via Toll-like receptor 4 (Tlr4), which in turn promotes a pro-inflammatory microenvironment leading to fatty liver formation and downregulates metabolic pathways, such as fatty acid metabolism and oxidative phosphorylation. Strikingly, ablation of Kupffer cells or TNFα blockade markedly abrogates the tumor-induced excess hepatic lipid droplet accumulation. We show that tumor implantation or pre-treatment with tumor EVPs decreases the expression of Cytochrome P450 genes and attenuates drug metabolism in mice. Notably, increased fatty livers and decreased Cytochrome P450 genes are observed in tumor-free livers in cancer patients. Thus, tumor-derived EVP uptake in the liver may lead to reduced tolerance of drug toxicity in cancer patients. Our results highlight the role of tumor EVPs in dysregulating hepatic functions and its potential to serve as therapeutic targets along with Kupffer cell-induced TNFα inhibition to prevent fatty liver formation and enhance anti-cancer chemotherapy. Overall design: Transcriptomic analysis (RNA sequencing) of the livers isolated from tumor (B16F10, or K7M2, or 67NR, or B16F1, or 4T1) -bearing mice, or EVP (B16F10-TE-EVPs, or K7M2-TE-EVPs, or B16F10-CL-EVPs, or K7M2-CL-EVPs, or B16F10_exomeres, or B16F10-Exo-S, or B16F10-Exo-L) -educated mice, and their respective controls. Transcriptomic analysis (RNA sequencing) of the murine primary hepatocytes after treatment with TNFalpha or PBS control.