{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T20:43:03Z","timestamp":1790023383801,"version":"4.0.1"},"reference-count":53,"publisher":"American Society for Clinical Investigation","issue":"7","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":47,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P01CA233452,R21AA025841,R01DK085252,R01DK138591"],"award-info":[{"award-number":["P01CA233452,R21AA025841,R01DK085252,R01DK138591"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH National Center for Advancing Translational Science","award":["UL1TR001881"],"award-info":[{"award-number":["UL1TR001881"]}]},{"DOI":"10.13039\/100013015","name":"Cedars-Sinai Medical Center","doi-asserted-by":"crossref","award":["the Center for Integrated Research in Cancer"],"award-info":[{"award-number":["the Center for Integrated Research in Cancer"]}],"id":[{"id":"10.13039\/100013015","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100013015","name":"Cedars-Sinai Medical Center","doi-asserted-by":"crossref","award":["Lifestyle Award,a Project Acceleration Award by the Cedars-Sinai Cancer Center"],"award-info":[{"award-number":["Lifestyle Award,a Project Acceleration Award by the Cedars-Sinai Cancer Center"]}],"id":[{"id":"10.13039\/100013015","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2023-00301850,RS-2023-00210489,RS-20240044114"],"award-info":[{"award-number":["RS-2023-00301850,RS-2023-00210489,RS-20240044114"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001424","name":"American Liver Foundation","doi-asserted-by":"crossref","award":["Postdoctoral Fellowship,Liver Scholar Award"],"award-info":[{"award-number":["Postdoctoral Fellowship,Liver Scholar Award"]}],"id":[{"id":"10.13039\/100001424","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>\n                      Has2\n                      <jats:sup>\u0394HSC<\/jats:sup>\n                    <\/jats:italic>\n                    mice, in which\n                    <jats:italic>Has2<\/jats:italic>\n                    is deleted from hepatic stellate cells.\n                    <jats:italic>\n                      Has2\n                      <jats:sup>\u0394HSC<\/jats:sup>\n                    <\/jats:italic>\n                    mice had reduced steatotic liver\u2013associated metastatic tumor growth of MC38 CRC cells, collagen and HA deposition, and CAF and M2 macrophage infiltration. We found that low\u2013molecular 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\n                    <jats:sup>+<\/jats:sup>\n                    T cells via programmed death\u2013ligand 1 and programmed cell death protein 1 (PD-1). HA synthesis inhibitors reduced steatotic liver\u2013associated metastasis of CRC, YAP expression, and CAF and M2 macrophage infiltration, and improved response to anti\u2013PD-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.\n                  <\/jats:p>","DOI":"10.1172\/jci180802","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T12:00:22Z","timestamp":1739448022000},"source":"Crossref","is-referenced-by-count":24,"title":["Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment"],"prefix":"10.1172","volume":"135","author":[{"given":"Yoon Mee","family":"Yang","sequence":"first","affiliation":[{"name":"Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."},{"name":"Department of Pharmacy,"},{"name":"Multidimensional Genomics Research Center, and"},{"name":"Innovative Drug Development Research Team for 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