Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment
Steatotic liver enhances liver metastasis of colorectal cancer (CRC), but this process is not fully understood. Steatotic liver induced by a high-fat diet 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 steatotic liver-associated metastatic tumor growth of MC38 CRC cells, collagen and HA deposition, and CAF and M2 macrophage infiltration. We found that 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 and M2 macrophages and CRC cells through CD44; these cells were associated with exhausted CD8+ T cells via programmed death-ligand 1 and programmed cell death protein 1 (PD-1). HA synthesis inhibitors reduced steatotic liver-associated metastasis of CRC, YAP expression, and CAF and M2 macrophage infiltration, and improved response to anti-PD-1 antibody. 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 CRC in the liver.
Authors
- Takashi Tsuchiya (ORCID: https://orcid.org/0000-0003-2594-1811)
- Yoon Mee Yang (ORCID: https://orcid.org/0000-0003-4281-9906)
- Shelly Chi-Loo Lu (ORCID: https://orcid.org/0000-0003-2128-5407)
- Edwin M. Posadas (ORCID: https://orcid.org/0000-0001-8649-1346)
- Ekihiro Seki (ORCID: https://orcid.org/0000-0002-9472-6085)
- Jee Hyung Lee
- GaEun Cho
- Sun Myoung Kim
- Vijay Pandyarajan (ORCID: https://orcid.org/0000-0002-8835-5601)
- Stephen J. Pandol (ORCID: https://orcid.org/0000-0003-0818-6017)
- Sungyong You (ORCID: https://orcid.org/0000-0003-3513-1783)
- Neil A. Bhowmick (ORCID: https://orcid.org/0000-0001-8747-5989)
- Alexander M. Xu (ORCID: https://orcid.org/0000-0003-4877-4358)
- Akil Abid Merchant (ORCID: https://orcid.org/0000-0001-7472-822X)
- Michitaka Matsuda (ORCID: https://orcid.org/0000-0003-1149-7924)
- Paul W. Noble (ORCID: https://orcid.org/0000-0001-7922-2295)
- Dianhua Jiang (ORCID: https://orcid.org/0000-0002-4508-3829)
- Michael Lewis (ORCID: https://orcid.org/0000-0002-1892-4127)
- Ji‐Eun Kim (ORCID: https://orcid.org/0000-0002-3643-2177)
- So Yeon Kim (ORCID: https://orcid.org/0000-0003-1319-6164)
- Zhijun Wang (ORCID: https://orcid.org/0000-0002-1857-4366)
- Jina Kim (ORCID: https://orcid.org/0000-0002-7662-6777)
- Alexandra Gangi
Institutions
- Cedars-Sinai Medical Center (US)
- Institute for Women's Policy Research (US)
- Union Hospital (HK)
- Kangwon National University (KR)
- Institute for Biomedicine (IT)
- ID Genomics (United States) (US)
- Samueli Institute (US)
- Cellular Therapeutics (United Kingdom) (GB)
- Cellular Research (United States) (US)
- VA Greater Los Angeles Healthcare System (US)
- Huazhong University of Science and Technology (CN)
- University of Maryland, College Park (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1172/jci180802
- Citations
- 10
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 9.36
Funders
- American Liver Foundation
- Cedars-Sinai Medical Center
- National Research Foundation of Korea
- National Institutes of Health