Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment

Zhijun Wang; So Yeon Kim; Wei Tu; Jieun Kim; Alexander Xu; Yoon Mee Yang; Michitaka Matsuda; Lien Reolizo; Takashi Tsuchiya; Sandrine Billet; Alexandra Gangi; Mazen Noureddin; Ben A Falk; Sungjin Kim; Wei Fan; Mourad Tighiouart; Sungyong You; Michael S Lewis; Stephen J Pandol; Dolores Di Vizio; Akil Merchant; Edwin M Posadas; Neil A Bhowmick; Shelly C Lu; Ekihiro Seki

doi:10.1016/j.cmet.2023.04.013

Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment

Cell Metab. 2023 Jul 11;35(7):1209-1226.e13. doi: 10.1016/j.cmet.2023.04.013. Epub 2023 May 11.

Authors

Zhijun Wang¹, So Yeon Kim², Wei Tu³, Jieun Kim², Alexander Xu⁴, Yoon Mee Yang⁵, Michitaka Matsuda², Lien Reolizo², Takashi Tsuchiya², Sandrine Billet⁴, Alexandra Gangi⁶, Mazen Noureddin⁷, Ben A Falk⁴, Sungjin Kim⁸, Wei Fan², Mourad Tighiouart⁸, Sungyong You⁹, Michael S Lewis¹⁰, Stephen J Pandol², Dolores Di Vizio⁹, Akil Merchant⁴, Edwin M Posadas⁴, Neil A Bhowmick⁴, Shelly C Lu², Ekihiro Seki¹¹

Affiliations

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.

PMID: 37172577
PMCID: PMC10524732 (available on 2024-07-11)
DOI: 10.1016/j.cmet.2023.04.013

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: CYR61; M2 macrophage; Rab27a; colon cancer; exosome; high-fat diet; liver metastasis; microRNA; non-alcoholic fatty liver disease; palmitate.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Colorectal Neoplasms* / metabolism
Extracellular Vesicles* / metabolism
Fatty Liver* / metabolism
Humans
Liver Neoplasms* / metabolism
MicroRNAs* / metabolism
Protein Serine-Threonine Kinases / metabolism
Tumor Microenvironment
Tumor Suppressor Proteins / metabolism

Substances

MicroRNAs
LATS2 protein, human
Protein Serine-Threonine Kinases
Tumor Suppressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding