Tumour extracellular vesicles and particles induce liver metabolic dysfunction

Area of Science:

• Oncology
• Hepatology
• Molecular Biology

Background:

• Cancer causes systemic organ dysfunction beyond metastasis.
• The liver is significantly affected, exhibiting inflammation, fatty liver, and metabolic dysregulation.
• Extrahepatic metastasis is associated with these systemic liver changes.

Purpose of the Study:

• To investigate the role of tumor-derived extracellular vesicles and particles (EVPs) in cancer-induced liver reprogramming.
• To identify mechanisms by which EVPs dysregulate hepatic function.
• To explore therapeutic strategies targeting EVPs and associated pathways.

Main Methods:

• Utilized mouse models and patient data to study liver changes in cancer.
• Identified and characterized tumor-derived EVPs, including exosomes and exomeres.
• Investigated the impact of EVP fatty acid cargo, particularly palmitic acid, on Kupffer cells and TNF secretion.
• Assessed the effects of Kupffer cell ablation, TNF blockade, and EVP depletion (Rab27a) on liver function and drug metabolism.
• Analyzed cytochrome P450 gene expression and drug metabolism in relation to EVPs and TNF.

Main Results:

• Tumor-derived EVPs are key mediators of cancer-induced liver reprogramming, leading to inflammation and fatty liver.
• Palmitic acid in EVPs induces Kupffer cell TNF secretion, promoting inflammation, suppressing metabolism, and causing fatty liver.
• Reducing EVP secretion via Rab27a depletion reversed hepatic reprogramming.
• TNF blockade or Kupffer cell ablation reduced tumor-induced fatty liver.
• EVPs diminished cytochrome P450 expression and attenuated drug metabolism in a TNF-dependent manner.
• Fatty liver and decreased cytochrome P450 were observed in cancer patients who developed metastasis.

Conclusions:

• Tumor-derived EVPs, particularly exomeres, dysregulate hepatic function through mechanisms involving TNF.
• Targeting EVP secretion and TNF signaling offers a strategy to prevent fatty liver and enhance chemotherapy efficacy.
• Metabolic reprogramming of the liver by EVPs may limit chemotherapy tolerance due to enhanced side effects.