{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:57:26Z","timestamp":1790740646511,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T00:00:00Z","timestamp":1730678400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005984","name":"Dr. Miriam and Sheldon G. 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The aim was to understand the crosstalk signalling pathways between hepatocytes and metastatic melanoma cells in the TME of MLiM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Hepatocytes and melanoma tumour cells of MLiM were assessed using transcriptomic NanoString GeoMx digital spatial profiling (NGDSP) assay. Functional assays were performed using normal hepatocytes and MLiM\u2010derived cell lines. Validation was performed using multiplex immunofluorescence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In NGDSP analysis adjacent normal hepatocytes (ANH) had higher CXCR4 and COL1A1\/2 levels than distant normal hepatocytes (DNH), while melanoma cells had higher TNF\u2010\u03b1 levels. In vitro, MLiM cell lines released TNF\u2010\u03b1 which upregulated CXCR4 and CXCL12 levels in ANH. CXCL12 activated CXCR4, which triggered AKT and NF\u03baB signalling pathways. Consequently, AKT signalling induced the upregulation of collagen type I. MLiM were significantly encircled by a shield of collagen, whereas other liver metastases showed reduced levels of collagen. Of all the liver metastasis analyzed, the presence of collagen in melanoma liver metastasis was associated with a reduction in tumour\u2010infiltrating lymphocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>MLiM modified ANH to increase collagen production and created a physical barrier. The collagen barrier was associated with a reduction of immune cell infiltration which could potentially deter MLiM immune surveillance and treatment responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Spatial analyses of melanoma liver metastasis show that adjacent normal hepatocytes have increased collagen\u2010type I levels.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Melanoma liver metastases tumour cells secrete enhanced levels of TNF\u2010\u03b1 to stimulate CXCR4\/CXCL12 upregulation in adjacent normal hepatocytes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Activation of CXCR4 promotes AKT and NF\u2010\u03baB signalling pathways to promote collagen\u2010type I secretion in adjacent normal hepatocytes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Elevated collagen levels were associated with reduced tumour\u2010infiltrating lymphocytes<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70067","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T02:13:26Z","timestamp":1730772806000},"source":"Crossref","is-referenced-by-count":8,"title":["Induced collagen type\u2010I secretion by hepatocytes of the melanoma liver metastasis is associated with a reduction in tumour\u2010infiltrating lymphocytes"],"prefix":"10.1002","volume":"14","author":[{"given":"Shodai","family":"Mizuno","sequence":"first","affiliation":[{"name":"Department of Translational Molecular Medicine Saint John's Cancer Institute (SJCI) at Providence Saint John's Health Center (SJHC)  Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matias A.","family":"Bustos","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Medicine Saint John's Cancer Institute (SJCI) at Providence Saint John's Health Center (SJHC)  Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Medicine Saint John's Cancer Institute (SJCI) at Providence Saint John's Health Center (SJHC)  Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kodai","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Medicine Saint John's Cancer Institute (SJCI) at Providence Saint John's Health Center (SJHC)  Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Furuhashi","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Medicine Saint John's Cancer Institute (SJCI) at Providence Saint John's Health Center (SJHC)  Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalda","family":"Naeini","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology at Providence SJHC  Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4098-7690","authenticated-orcid":false,"given":"Xiaowei","family":"Xu","sequence":"additional","affiliation":[{"name":"Abramson Cancer Center, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton J","family":"Bilchik","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal and Hepatobiliary Surgery, Providence SJHC  Santa Monica California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1915-3683","authenticated-orcid":false,"given":"Dave S. 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