Highlights in Cancer Research: August 2023

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

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9. Tumour extracellular vesicles and particles induce liver metabolic dysfunction

Wang, G., Li, J. et al. Nature. 618: 374–382 (2023).
doi: 10.1038/s41586-023-06114-4.

Summary of the findings

Cancer is a systemic disease where primary tumours disrupt host homeostasis through metastasis and the release of soluble factors, such as proteins, metabolites, hormones, and extracellular vesicles and particles (EVPs) into the circulation, affecting both local and distant tissues and organs.

Wang and colleagues discovered that tumour-derived EVPs containing saturated fatty acids, in particular palmitic acid, can be transported to liver resident macrophages, Kupffer cells, triggering the release of TNF via TLR4. TNF-induced immune responses and fatty liver generation occurred in both tumour-bearing mice and cancer patients with extrahepatic metastasis. TNF also suppressed the expression of genes encoding the cytochrome P450 enzymes crucial for drug metabolism, thereby impairing drug metabolism in the livers of tumour-bearing mice. Importantly, the livers of pancreatic cancer patients with extrahepatic metastasis also exhibited downregulated cytochrome P450 enzymes. Treatment of mice with tumour-derived EVPs increased chemotoxicity, providing valuable insights into the diminished effectiveness and reduced tolerance to chemotherapy observed in cancer patients, even in the absence of liver metastasis. Notably, the abundant, non-membranous tumour-derived EVP subpopulation first described by the Lyden group in 2018, the exomeres, had a greater impact on promoting fatty liver disease than exosomes, suggesting that exomeres play a major role in dysregulating liver metabolic function.

EVPs derived from cancers with extrahepatic metastatic tropism induce lipid droplet accumulation and suppress cytochrome P450 gene expression in the liver, leading to fatty liver generation and impaired liver drug metabolism, respectively. KC, Kupffer cell. TLR4, Toll-like receptor 4. LD, lipid droplet. CYP, cytochrome P450 enxymes. PA, palmitic acid, SFAs, saturated fatty acids.

Future impact

This groundbreaking study unveils a novel perspective on the systemic effects of cancer, showing that multiple types of cancers with extrahepatic metastatic tropism can induce fatty liver generation and diminish drug metabolism in the liver. These findings suggest that blocking TNF locally in the liver or inhibiting palmitic acid production and thus preventing its packaging in tumour-derived EVPs could prevent fatty liver disease, improving drug metabolism and chemotherapy efficacy in cancer patients. Overall, this study has expanded our understanding of the mechanisms through which cancer exerts its systemic effects and presents potential avenues for enhancing anti-cancer treatment.

Read more in Nature