{"doi":"10.1172/jci180802","title":"Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment","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.","journal":"Journal of Clinical Investigation","year":2025,"id":510579,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":802110,"name":"Ji‐Eun Kim","orcid":"0000-0002-3643-2177","position":1,"is_corresponding":false},{"id":748534,"name":"Zhijun Wang","orcid":"0000-0002-1857-4366","position":2,"is_corresponding":false},{"id":870401,"name":"Jina Kim","orcid":"0000-0002-7662-6777","position":3,"is_corresponding":false},{"id":1263206,"name":"So Yeon Kim","orcid":"0000-0003-1319-6164","position":4,"is_corresponding":false},{"id":1367681,"name":"Gyu Jeong Cho","orcid":null,"position":5,"is_corresponding":false},{"id":891258,"name":"Jee Hyung Lee","orcid":null,"position":6,"is_corresponding":false},{"id":891255,"name":"Sun Myoung Kim","orcid":null,"position":7,"is_corresponding":false},{"id":1016479,"name":"Takashi Tsuchiya","orcid":"0000-0003-2594-1811","position":8,"is_corresponding":false},{"id":251733,"name":"Michitaka Matsuda","orcid":"0000-0003-1149-7924","position":9,"is_corresponding":false},{"id":1366971,"name":"Vijay Pandyarajan","orcid":"0000-0002-8835-5601","position":10,"is_corresponding":false},{"id":227742,"name":"Stephen J. 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