@article{513c9653a3eb499d9a65d1aaa7444737,
title = "Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment",
abstract = "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.",
keywords = "colon cancer, CYR61, exosome, high-fat diet, liver metastasis, M2 macrophage, microRNA, non-alcoholic fatty liver disease, palmitate, Rab27a, Humans, Tumor Microenvironment, Extracellular Vesicles/metabolism, Fatty Liver/metabolism, Colorectal Neoplasms/metabolism, Protein Serine-Threonine Kinases/metabolism, Tumor Suppressor Proteins/metabolism, MicroRNAs/metabolism, Liver Neoplasms/metabolism",
author = "Zhijun Wang and Kim, {So Yeon} and Wei Tu and Jieun Kim and Alexander Xu and Yang, {Yoon Mee} and Michitaka Matsuda and Lien Reolizo and Takashi Tsuchiya and Sandrine Billet and Alexandra Gangi and Mazen Noureddin and Falk, {Ben A.} and Sungjin Kim and Wei Fan and Mourad Tighiouart and Sungyong You and Lewis, {Michael S.} and Pandol, {Stephen J.} and {Di Vizio}, Dolores and Akil Merchant and Posadas, {Edwin M.} and Bhowmick, {Neil A.} and Lu, {Shelly C.} and Ekihiro Seki",
note = "Funding Information: This work is supported by the National Institutes of Health (P01CA233452to E.S. N.A.B. S.J.P. E.M.P. and S.C.L.; R21AA025841 to E.S. and S.C.L.; R01DK085252 to E.S.), the Center for Integrated Research in Cancer and Lifestyle Award (to E.S.), and a Project Acceleration Award by the Cedars-Sinai Cancer Center at Cedars-Sinai Medical Center (to E.S. and S.J.P.). The authors acknowledge the Imaging Mass Cytometry Research Core, the Biobank and Research Pathology Core, and the Applied Genomics, Computation & Translational Research Core at Cedars-Sinai Cancer and Cedars-Sinai Medical Center. Conceptualization, E.S. and Z.W.; methodology, Z.W. S.Y.K. J.K. A.X. S.B. Y.M.Y. A.M. S.Y. and D.D.V.; investigation, Z.W. S.Y.K. J.K. W.T. M.M. L.R. T.T. S.B. B.A.F. and W.F.; formal analysis, Z.W. S.Y.K. J.K. A.X. Y.M.Y. S.K. M.T. and E.S.; writing – original draft, Y.M.Y. and E.S.; writing – review & editing, S.J.P. N.A.B. S.C.L. Y.M.Y. and E.S.; funding acquisition, E.S. E.M.P. N.A.B. and S.C.L.; resources, M.N. A.G. M.S.L. A.M. and E.M.P.; supervision, E.S. 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. We support inclusive, diverse, and equitable conduct of research. Funding Information: This work is supported by the National Institutes of Health ( P01CA233452 to E.S., N.A.B., S.J.P., E.M.P., and S.C.L.; R21AA025841 to E.S. and S.C.L.; R01DK085252 to E.S.), the Center for Integrated Research in Cancer and Lifestyle Award (to E.S.), and a Project Acceleration Award by the Cedars-Sinai Cancer Center at Cedars-Sinai Medical Center (to E.S. and S.J.P.). The authors acknowledge the Imaging Mass Cytometry Research Core, the Biobank and Research Pathology Core, and the Applied Genomics, Computation & Translational Research Core at Cedars-Sinai Cancer and Cedars-Sinai Medical Center. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = jul,
day = "11",
doi = "10.1016/j.cmet.2023.04.013",
language = "English (US)",
volume = "35",
pages = "1209--1226.e13",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "7",
}