Tumor-derived extracellular vesicles and particles systemically promote Kupffer cell-induced fatty liver disease and drug-metabolizing 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 TNFα via Toll-like receptor 4, which in turn promotes a pro-inflammatory microenvironment leading to fatty liver disease 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 disease and enhance anti-cancer chemotherapy. Comparative RNA-seq analysis of the liver of patients with localized pancreatic cancer (PC), who did not develop liver metastasis during subsequent follow-up, with the liver of patients with non-cancerous lesions of the pancreas (PanIN, retention cysts, duodenal adenoma), or normal liver adjacent to resected hepatocellular adenoma