Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment

• Published in: Cell metabolism Vol. 35; no. 7; pp. 1209 - 1226.e13
• Main Authors: Wang, Zhijun, Kim, So Yeon, Tu, Wei, Kim, Jieun, Xu, Alexander, Yang, Yoon Mee, Matsuda, Michitaka, Reolizo, Lien, Tsuchiya, Takashi, Billet, Sandrine, Gangi, Alexandra, Noureddin, Mazen, Falk, Ben A., Kim, Sungjin, Fan, Wei, Tighiouart, Mourad, You, Sungyong, Lewis, Michael S., Pandol, Stephen J., Di Vizio, Dolores, Merchant, Akil, Posadas, Edwin M., Bhowmick, Neil A., Lu, Shelly C., Seki, Ekihiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-07-2023
• Subjects: colon cancer; Colorectal Neoplasms - metabolism; CYR61; exosome; Extracellular Vesicles - metabolism; Fatty Liver - metabolism; high-fat diet; Humans; liver metastasis; Liver Neoplasms - metabolism; M2 macrophage; microRNA; MicroRNAs - metabolism; non-alcoholic fatty liver disease; palmitate; Protein Serine-Threonine Kinases - metabolism; Rab27a; Tumor Microenvironment; Tumor Suppressor Proteins - metabolism; liver metastasis; M2 macrophage; non-alcoholic fatty liver disease; palmitate; colon cancer; high-fat diet; Rab27a; microRNA; exosome; CYR61
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2023.04.013

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.
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•Fatty liver upregulates hepatic Rab27a expression, promoting EV production•Fatty liver-derived EVs enhance YAP activity in CRC liver metastasis•Enhanced YAP induces CYR61 expression in CRC liver metastasis•CYR61 modulates the immunosuppressive environment in CRC liver metastasis
Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Wang et al. demonstrate that fatty liver enhances the production of hepatocyte-derived extracellular vesicles that promote the progression of CRC liver metastasis by augmenting Yes-associated protein signaling and the immunosuppressive tumor microenvironment.