Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment.

Wang Z, Kim SY, Tu W, Kim J, Xu A, Yang YM, Matsuda M, Reolizo L, Tsuchiya T, Billet S

Cell Metab 2023

1. Cell Metab. 2023 Jul 11;35(7):1209-1226.e13. doi: 10.1016/j.cmet.2023.04.013. Epub 2023 May 11. Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment. Wang Z(1), Kim SY(2), Tu W(3), Kim J(2), Xu A(4), Yang YM(5), Matsuda M(2), Reolizo L(2), Tsuchiya T(2), Billet S(4), Gangi A(6), Noureddin M(7), Falk BA(4), Kim S(8), Fan W(2), Tighiouart M(8), You S(9), Lewis MS(10), Pandol SJ(2), Di Vizio D(9), Merchant A(4), Posadas EM(4), Bhowmick NA(4), Lu SC(2), Seki E(11). Author information: (1)Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. (2)Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (3)Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China. (4)Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (5)Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea. (6)Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (7)Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Houston Methodist Hospital, Houston Research Institute, Houston, TX 77030, USA. (8)Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (9)Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (10)Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Pathology, Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, CA 90073, USA. (11)Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: ekihiro.seki@cshs.org. Comment in Trends Cell Biol. 2023 Sep;33(9):729-731. doi: 10.1016/j.tcb.2023.07.001. Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment. Fatty liver upregulated Rab27a expression, which facilitated EV production from hepatocytes. In the liver, these EVs transferred YAP signaling-regulating microRNAs to cancer cells to augment YAP activity by suppressing LATS2. Increased YAP activity in CRC liver metastasis with fatty liver promoted cancer cell growth and an immunosuppressive microenvironment by M2 macrophage infiltration through CYR61 production. Patients with CRC liver metastasis and fatty liver had elevated nuclear YAP expression, CYR61 expression, and M2 macrophage infiltration. Our data indicate that fatty liver-induced EV-microRNAs, YAP signaling, and an immunosuppressive microenvironment promote the growth of CRC liver metastasis. Copyright © 2023 Elsevier Inc. All rights reserved. DOI: 10.1016/j.cmet.2023.04.013 PMCID: PMC10524732 PMID: 37172577 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests M.N. is a member of the advisory board of Altimmune, BI, BMS, Cytodyn, 89BIO, EchoSens, Gilead, GSK, Madrgial, Merck, Novo Nordisk, OWL, Prespecturm, Pfizer, Roche Diagnostic, and Siemens, Terns and Takeda; received research support from Allergan, Akero, BMS, Gilead, Galectin, Genfit, GSK, Conatus, Corcept, Enanta, Madrigal, Novartis, Novo Nordisk, Shire, Takeda, Terns, Viking, and Zydus; and is a stockholder in Anaetos, Rivus Pharma, CIMA, ChronWell, and Viking.