Tumour extracellular vesicles and particles induce liver metabolic dysfunction PMID: 37225988

ADC Targets in Oncology

2026-04-10

Tumour extracellular vesicles and particles induce liver metabolic dysfunction

Nature. 2023 May 24. doi: 10.1038/s41586-023-06114-4.

Gang Wang ^# ¹ , Jianlong Li ^# ¹ ² , Linda Bojmar ¹ ³ , Haiyan Chen ¹ ⁴ ⁵ , Zhong Li ⁶ , Gabriel C Tobias ¹ , Mengying Hu ¹ , Edwin A Homan ⁷ , Serena Lucotti ¹ , Fengbo Zhao ¹ ⁸ , Valentina Posada ⁹ , Peter R Oxley ¹⁰ , Michele Cioffi ¹ , Han Sang Kim ¹ ¹¹ , Huajuan Wang ¹ , Pernille Lauritzen ¹ , Nancy Boudreau ¹ , Zhanjun Shi ² , Christin E Burd ⁹ , Jonathan H Zippin ¹² , James C Lo ⁷ , Geoffrey S Pitt ⁷ , Jonathan Hernandez ¹³ ¹⁴ , Constantinos P Zambirinis ¹³ ¹⁵ , Michael A Hollingsworth ¹⁶ , Paul M Grandgenett ¹⁶ , Maneesh Jain ¹⁶ , Surinder K Batra ¹⁶ , Dominick J DiMaio ¹⁷ , Jean L Grem ¹⁸ , Kelsey A Klute ¹⁸ , Tanya M Trippett ¹⁹ , Mikala Egeblad ²⁰ , Doru Paul ²¹ , Jacqueline Bromberg ²² , David Kelsen ²³ , Vinagolu K Rajasekhar ²⁴ , John H Healey ²⁴ , Irina R Matei ¹ , William R Jarnagin ¹³ , Robert E Schwartz ²⁵ , Haiying Zhang ²⁶ , David Lyden ²⁷

Affiliations

1. Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
2. Department of Orthopedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
3. Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
4. Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
5. Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, China.
6. Duke Proteomics and Metabolomics Shared Resource, Duke University School of Medicine, Durham, NC, USA.
7. Cardiovascular Research Institute and Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
8. Basic Medical Research Center, Medical School of Nantong University, Nantong, China.
9. Departments of Molecular Genetics, Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
10. Samuel J. Wood Library, Weill Cornell Medicine, New York, NY, USA.
11. Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Brain Korea 21 FOUR Project for Medical Science, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
12. Department of Dermatology, Weill Cornell Medical College of Cornell University, New York, NY, USA.
13. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
14. Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
15. Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
16. Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
17. Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
18. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
19. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
20. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
21. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
22. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
23. Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
24. Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
25. Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA. [email protected].
26. Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. [email protected].
27. Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. [email protected].
# Contributed equally.

Abstract

Cancer alters the function of multiple organs beyond those targeted by metastasis^1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and Oxidative Phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished Cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased Cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic Cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with Cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.