ArticleThe Journal of clinical investigation2025
Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Article
- LOXL4: a key regulatory factor at the intersection of fibrosis and tumor progression.Human cell · 2026Review
- From steatosis to metastasis: microenvironmental reprogramming of the liver in metabolic dysfunction-associated steatotic liver disease.Clinical and molecular hepatology · 2026Review
- Development and external validation of a preoperative CT body composition-based model for predicting postoperative metastasis in colorectal cancer: a multicenter retrospective cohort study.Abdominal radiology (New York) · 2026Article
- Cancer-associated fibroblasts as a critical driver in tumor metastasis: The mechanisms and future perspectives.iScience · 2026Review
- The myofascial rheostat: hyaluronan molecular weight dynamics and purinergic signalling as a physiological feedback system.Frontiers in physiology · 2026Review
- Metabolic dysfunction-associated steatotic liver disease and immune checkpoint inhibitor response in gastrointestinal liver metastases: current evidence and future directions.Frontiers in nutrition · 2026Review
- Navigating the Tumor Microenvironment in Colorectal Liver Metastasis: Barriers to Therapy and Emerging Opportunities.Oncology research · 2026Review
- Understanding Fascial Tissue on the Molecular Level-How Its Unique Properties Enable Adaptation or Dysfunction.International journal of molecular sciences · 2025Review
- Extracellular vesicles cargo orchestration in colorectal cancer: immune evasion, stromal remodeling, and therapeutic frontiers.Molecular cancer · 2025Review
- The hepatic macrophage: a key regulator of liver metastatic tumor microenvironment through cell crosstalk.Journal of translational medicine · 2025Review
- SMYD3-CDCP1 Axis Drives EMT and CAF Activation in Colorectal Cancer and Is Targetable for Oxaliplatin Sensitization.Biomedicines · 2025Article
- Cancer-Associated Fibroblasts: Origin, Classification, Tumorigenicity, and Targeting for Cancer Therapy.MedComm · 2025Review
- Hyaluronic Acid in Liver Fibrosis: Role in Inflammation, Tissue Remodeling, and Disease Progression.International journal of molecular sciences · 2025Review
- Hepatic Stellate Cells Functional Heterogeneity in Liver Cancer.Seminars in liver disease · 2025Review
- Extracellular matrix remodeling fibroblasts govern the tumor microenvironment disparity between adenomatous lesions and adenocarcinoma in gallbladder.Frontiers in immunology · 2025Article
Corrections and comments
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Authors and funding
23 authors.
Funding
Abstract
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.
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