Metastatic Tumor Growth in Steatotic Liver is Promoted by HAS2-Mediated Fibrotic Tumor Microenvironment

Yoon Mee Yang; Jieun Kim; Zhijun Wang; Jina Kim; So Yeon Kim; Gyu Jeong Cho; Jee Hyung Lee; Sun Myoung Kim; Takashi Tsuchiya; Michitaka Matsuda; Vijay Pandyarajan; Stephen J. Pandol; Michael S. Lewis; Alexandra Gangi; Paul W. Noble; Dianhua Jiang; Akil Merchant; Edwin M. Posadas; Neil A. Bhowmick; Shelly C. Lu; Sungyong You; Alexander M. Xu; Ekihiro Seki

doi:10.1172/JCI180802

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Yang, Y. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Kim, J. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Wang, Z. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Kim, J. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Kim, S. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Cho, G. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Lee, J. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Kim, S. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Tsuchiya, T. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Matsuda, M. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Pandyarajan, V. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Pandol, S. in: JCI | PubMed | Google Scholar |

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Lewis, M. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Gangi, A. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Noble, P. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Jiang, D. in: JCI | PubMed | Google Scholar |

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Merchant, A. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Posadas, E. in: JCI | PubMed | Google Scholar |

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Bhowmick, N. in: JCI | PubMed | Google Scholar |

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Lu, S. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by You, S. in: JCI | PubMed | Google Scholar |

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Xu, A. in: JCI | PubMed | Google Scholar

¹Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

²Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

³Department of Pharmacy, Kangwon National University, Chuncheon, Korea, Republic of

⁴Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁵Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁶Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America

Find articles by Seki, E. in: JCI | PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI180802.
Copyright © 2025, Yang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published February 13, 2025 - Version history

Steatotic liver enhances liver metastasis of colorectal cancer, but this process is not fully understood. Steatotic liver induced by a high-fat diet (HFD) increases cancer-associated fibroblast (CAF) infiltration and collagen and hyaluronic acid (HA) production. We investigated the role of HA synthase 2 (HAS2) in the fibrotic tumor microenvironment in steatotic liver using Has2^ΔHSC mice, in which Has2 is deleted from hepatic stellate cells. Has2^ΔHSC mice had reduced steatotoic liver-associated metastatic tumor growth of MC38 colorectal cancer cells, collagen and HA deposition, and CAF and M2 macrophage infiltration. We found low-molecular-weight HA activates yes-associated protein (YAP) in cancer cells, which then releases connective tissue growth factor to further activate CAFs for HAS2 expression. Single-cell analyses revealed a link between CAF-derived HAS2 with M2 macrophages and colorectal cancer cells through CD44; these cells associated with exhausted CD8 T cells via programmed death-ligand 1 and programmed cell death protein 1. The HA synthesis inhibitors reduced steatotic liver-associated metastasis of colorectal cancer, YAP expression, CAF and M2 macrophage infiltration. In conclusion, steatotic liver modulates a fibrotic tumor microenvironment to enhance metastatic cancer activity through a bidirectional regulation between CAFs and metastatic tumors, enhancing the metastatic potential of colorectal cancer in the liver.

Version 1 (February 13, 2025): In-Press Preview

Metastatic Tumor Growth in Steatotic Liver is Promoted by HAS2-Mediated Fibrotic Tumor Microenvironment

Article tools

Metrics

Go to

Metastatic Tumor Growth in Steatotic Liver is Promoted by HAS2-Mediated Fibrotic Tumor Microenvironment

Article tools

Metrics

Go to

Sign up for email alerts