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J. Clin. Invest., Feb 13 2025, e180802 | https://doi.org/10.1172/JCI180802
Metastatic Tumor Growth in Steatotic Liver is Promoted by HAS2-Mediated Fibrotic Tumor Microenvironment
Yoon Mee Yang1,2,3,4#, Jieun Kim1,#, Zhijun Wang1,5,##, Jina Kim6,7,8,##, So Yeon Kim1, Gyu Jeong Cho2,4, Jee Hyung Lee2, Sun Myoung Kim2,4, Takashi Tsuchiya1, Michitaka Matsuda1, Vijay Pandyarajan1, Stephen J. Pandol1, Michael S. Lewis9,10, Alexandra Gangi11, Paul W. Noble12, Dianhua Jiang12, Akil Merchant6,13, Edwin M. Posada6,14, Neil A. Bhowmick6,14, Shelly C. Lu1, Sungyong You6,7,8,*, Alexander M. Xu6,15,16,*, Ekihiro Seki1,6,15,*
1Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
2Department of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea,
3Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, Republic of Korea,
4Innovative Drug Development Research Team for Intractable Diseases (BK21 plus), Kangwon National University, Chuncheon, 24341, Republic of Korea,
5Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,
6Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
7Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
8Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
10Department of Pathology, Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, CA 90073, USA,
11Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
12Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048,USA,
13Division of Hematology and Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
14Division of Medical Oncology, Department of Medicine, CedarsSinai Medical Center, Los Angeles, CA 90048, USA,
15Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
16Fischell Department of Bioengineering, A. James Clark School of Engineering, University of Maryland, College Park, MD 20742
# YMY and Jieun K are the co-first authors and contributed equally to this work.
## ZW and Jina K contributed equally as the second authors of this work.
*Correspondence to: Eihiro Seki, M.D., Ph.D., Alexander M. Xu, PhD, Sungyong You, PhD
1Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
2Department of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea,
3Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, Republic of Korea,
4Innovative Drug Development Research Team for Intractable Diseases (BK21 plus), Kangwon National University, Chuncheon, 24341, Republic of Korea,
5Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,
6Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
7Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
8Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
9Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
10Department of Pathology, Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, CA 90073, USA,
11Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
12Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048,USA,
13Division of Hematology and Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
14Division of Medical Oncology, Department of Medicine, CedarsSinai Medical Center, Los Angeles, CA 90048, USA,
15Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA,
16Fischell Department of Bioengineering, A. James Clark School of Engineering, University of Maryland, College Park, MD 20742
# YMY and Jieun K are the co-first authors and contributed equally to this work.
## ZW and Jina K contributed equally as the second authors of this work.
*Correspondence to: Eihiro Seki, M.D., Ph.D., Alexander M. Xu, PhD, Sungyong You, PhD
Abstract
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 Has2ΔHSC mice, in which Has2 is deleted from hepatic stellate cells. Has2ΔHSC 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.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-14)
- 국내+국외 연구진
- 생명과학 > 노화/암생물학
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