Tumor-Derived Extracellular Vesicles and Particles Inhibit Liver Function

Cancers reprogram the surrounding primary tumor microenvironment while exerting effects on remote tissues through the systemic release of soluble factors. Extracellular vesicles and particles (EVP) released from primary tumors can localize to organs, such as the liver, and establish premetastatic niches, but how tumor-derived EVPs impact liver function independently of liver metastasis is not well understood. Wang, Li, and colleagues sought to answer this question by assessing liver function in orthotopic murine models of melanoma and osteosarcoma that preferentially metastasized to the lung. Transcriptomic analysis of metastasis-free livers demonstrated that livers from tumor-bearing mice differentially expressed genes involved in inflammation, fatty acid metabolism, and oxidative phosphorylation, whereas tissue staining and mass spectrometric analyses indicated that the presence of remote tumors promoted lipid droplet accumulation and elevated levels of multiple lipid species, supporting that tumors systemically induced fatty liver generation and altered immune regulation within the liver. Moreover, clinical relevance of such phenotypes was demonstrated, as fatty liver formation was also observed in patients with pancreatic cancer who developed nonliver metastasis. Intravenous injection of EVPs derived from murine tumor explants into mice was sufficient to recapitulate the phenotypes observed in tumor-bearing mice, suggesting that tumor-derived EVPs were the primary drivers of liver metabolic dysfunction. EVPs were predominantly taken up by Cd11b⁺F4/80⁺ resident liver macrophages known as Kupffer cells, and depletion of Kupffer cells via clodronate administration prevented EVP-induced lipid droplet accumulation within the liver. Compared with EVPs secreted by nontumor control cells, the cargo within tumor-derived EVPs was enriched for fatty acids, such as palmitic acid, which is known to trigger proinflammatory cytokine secretion by Kupffer cells. Indeed, EVP-packaged palmitic acid activated expression of the inflammatory cytokine encoded by Tnf within Kupffer cells in a manner dependent on pattern recognition receptor signaling through TLR4. In addition, tumor-derived EVPs repressed the expression of cytochrome P450 (Cyp) enzymes within the liver and enhanced the toxic side effects of chemotherapies metabolized by Cyp. In summary, these findings highlight how remote primary tumors can impact liver function and decrease drug metabolism, which leads to enhanced chemotoxicity and also suggests that targeting tumor-derived EVPs and their induced systemic effects could improve clinical outcomes.

Wang G, Li J, Bojmar L, Chen H, Li Z, Tobias GC, et al. Tumour extracellular vesicles and particles induce liver metabolic dysfunction. Nature 2023 May 24 [Epub ahead of print].

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