TY - JOUR
T1 - Tumour extracellular vesicles and particles induce liver metabolic dysfunction
AU - Wang, Gang
AU - Li, Jianlong
AU - Bojmar, Linda
AU - Chen, Haiyan
AU - Li, Zhong
AU - Tobias, Gabriel C.
AU - Hu, Mengying
AU - Homan, Edwin A.
AU - Lucotti, Serena
AU - Zhao, Fengbo
AU - Posada, Valentina
AU - Oxley, Peter R.
AU - Cioffi, Michele
AU - Kim, Han Sang
AU - Wang, Huajuan
AU - Lauritzen, Pernille
AU - Boudreau, Nancy
AU - Shi, Zhanjun
AU - Burd, Christin E.
AU - Zippin, Jonathan H.
AU - Lo, James C.
AU - Pitt, Geoffrey S.
AU - Hernandez, Jonathan
AU - Zambirinis, Constantinos P.
AU - Hollingsworth, Michael A.
AU - Grandgenett, Paul M.
AU - Jain, Maneesh
AU - Batra, Surinder K.
AU - DiMaio, Dominick J.
AU - Grem, Jean L.
AU - Klute, Kelsey A.
AU - Trippett, Tanya M.
AU - Egeblad, Mikala
AU - Paul, Doru
AU - Bromberg, Jacqueline
AU - Kelsen, David
AU - Rajasekhar, Vinagolu K.
AU - Healey, John H.
AU - Matei, Irina R.
AU - Jarnagin, William R.
AU - Schwartz, Robert E.
AU - Zhang, Haiying
AU - Lyden, David
N1 - Funding Information:
The authors acknowledge the Genomics Resource Core Facility (Weill Cornell Medicine), Electron Microscopy and Histology Core Facility (Weill Cornell Medicine), Molecular Cytology Core Facility (Memorial Sloan Kettering Cancer Center, MSKCC) and Laboratory of Comparative Pathology (MSKCC) for their high-quality service. The authors also acknowledge technical support from Wyatt Technology. The authors thank members of the Lyden laboratory for insightful discussions. The authors gratefully acknowledge support from the National Cancer Institute (CA232093, CA163117 and CA207983 to D.L. and CA218513 to D.L. and H.Z.), the Thompson Family Foundation (to D.L. and D.K.), the Tortolani Foundation (to D.L. and J.B.), the Pediatric Oncology Experimental Therapeutics Investigator’s Consortium, the Malcolm Hewitt Weiner Foundation, the Manning Foundation, the Sohn Foundation, the AHEPA Vth District Cancer Research Foundation, the Children’s Cancer and Blood Foundation, the Hartwell Foundation (to D.L.), the National Institutes of Health (R01CA234614, 2R01AI107301, R01CA234614 and R01DK121072 to R.E.S.), the United States Department of Defense (W81XWH-21-1-0978 to R.E.S.), the Paul G. Allen Family Foundation UWSC13448 (to R.E.S.), the National Natural Science Foundation of China (81902730 to J.L.), Guangdong Foundation of Medical Science and Technology (A2019213 to J.L.), China Scholarship Council (CSC No. 202008440567 to J.L.), the Swedish Cancer Society Pancreatic Cancer Fellowship (to L.B.), the Lions International Postdoctoral fellowship (to L.B.), the Sweden-America stipend (to L.B.), and the fellowship from Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center of Memorial Sloan Kettering Cancer Center (to C.P.Z.). The part of the research involved in developing osteosarcoma PDXs and tumour imaging was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to MSKCC, the National Institutes of Health (R01CA237213 to C.E.B and V.P., and R01CA254036 to S.K.B.). R.E.S. is an Irma Hirschl Trust Research Award Scholar. Schematic models were generated in part using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license, with further modifications.
Funding Information:
The authors acknowledge the Genomics Resource Core Facility (Weill Cornell Medicine), Electron Microscopy and Histology Core Facility (Weill Cornell Medicine), Molecular Cytology Core Facility (Memorial Sloan Kettering Cancer Center, MSKCC) and Laboratory of Comparative Pathology (MSKCC) for their high-quality service. The authors also acknowledge technical support from Wyatt Technology. The authors thank members of the Lyden laboratory for insightful discussions. The authors gratefully acknowledge support from the National Cancer Institute (CA232093, CA163117 and CA207983 to D.L. and CA218513 to D.L. and H.Z.), the Thompson Family Foundation (to D.L. and D.K.), the Tortolani Foundation (to D.L. and J.B.), the Pediatric Oncology Experimental Therapeutics Investigator’s Consortium, the Malcolm Hewitt Weiner Foundation, the Manning Foundation, the Sohn Foundation, the AHEPA Vth District Cancer Research Foundation, the Children’s Cancer and Blood Foundation, the Hartwell Foundation (to D.L.), the National Institutes of Health (R01CA234614, 2R01AI107301, R01CA234614 and R01DK121072 to R.E.S.), the United States Department of Defense (W81XWH-21-1-0978 to R.E.S.), the Paul G. Allen Family Foundation UWSC13448 (to R.E.S.), the National Natural Science Foundation of China (81902730 to J.L.), Guangdong Foundation of Medical Science and Technology (A2019213 to J.L.), China Scholarship Council (CSC No. 202008440567 to J.L.), the Swedish Cancer Society Pancreatic Cancer Fellowship (to L.B.), the Lions International Postdoctoral fellowship (to L.B.), the Sweden-America stipend (to L.B.), and the fellowship from Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center of Memorial Sloan Kettering Cancer Center (to C.P.Z.). The part of the research involved in developing osteosarcoma PDXs and tumour imaging was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to MSKCC, the National Institutes of Health (R01CA237213 to C.E.B and V.P., and R01CA254036 to S.K.B.). R.E.S. is an Irma Hirschl Trust Research Award Scholar. Schematic models were generated in part using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license, with further modifications.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/6/8
Y1 - 2023/6/8
N2 - Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. 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.
AB - Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85160220023&partnerID=8YFLogxK
U2 - 10.1038/s41586-023-06114-4
DO - 10.1038/s41586-023-06114-4
M3 - Article
C2 - 37225988
AN - SCOPUS:85160220023
SN - 0028-0836
VL - 618
SP - 374
EP - 382
JO - Nature
JF - Nature
IS - 7964
ER -