{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:21:19Z","timestamp":1787242879805,"version":"build-2736575974"},"reference-count":65,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T00:00:00Z","timestamp":1712707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund, FWF","doi-asserted-by":"publisher","award":["P31720-B33"],"award-info":[{"award-number":["P31720-B33"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund, FWF","doi-asserted-by":"publisher","award":["Doc 59-B33"],"award-info":[{"award-number":["Doc 59-B33"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"FWF IPPTO project","doi-asserted-by":"publisher","award":["P31720-B33"],"award-info":[{"award-number":["P31720-B33"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"FWF IPPTO project","doi-asserted-by":"publisher","award":["Doc 59-B33"],"award-info":[{"award-number":["Doc 59-B33"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"L\u2019Or\u00e9al Austria \/Austrian Academy of Science\/UNESCO Austria","award":["P31720-B33"],"award-info":[{"award-number":["P31720-B33"]}]},{"name":"L\u2019Or\u00e9al Austria \/Austrian Academy of Science\/UNESCO Austria","award":["Doc 59-B33"],"award-info":[{"award-number":["Doc 59-B33"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The activation of the receptor tyrosine kinase Axl by Gas6 is a major driver of tumorigenesis. Despite recent insights, tumor cell-intrinsic and -extrinsic Axl functions are poorly understood in hepatocellular carcinoma (HCC). Thus, we analyzed the cell-specific aspects of Axl in liver cancer cells and in the tumor microenvironment. We show that tumor-intrinsic Axl expression decreased the survival of mice and elevated the number of pulmonary metastases in a model of resection-based tumor recurrence. Axl expression increased the invasion of hepatospheres by the activation of Akt signaling and a partial epithelial-to-mesenchymal transition (EMT). However, the liver tumor burden of Axl+\/+ mice induced by diethylnitrosamine plus carbon tetrachloride was reduced compared to systemic Axl\u2212\/\u2212 mice. Tumors of Axl+\/+ mice were highly infiltrated with cytotoxic cells, suggesting a key immune-modulatory role of Axl. Interestingly, hepatocyte-specific Axl deficiency did not alter T cell infiltration, indicating that these changes are independent of tumor cell-intrinsic Axl. In this context, we observed an upregulation of multiple chemokines in Axl+\/+ compared to Axl\u2212\/\u2212 tumors, correlating with HCC patient data. In line with this, Axl is associated with a cytotoxic immune signature in HCC patients. Together these data show that tumor-intrinsic Axl expression fosters progression, while tumor-extrinsic Axl expression shapes an inflammatory microenvironment.<\/jats:p>","DOI":"10.3390\/ijms25084202","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T03:29:04Z","timestamp":1712806144000},"page":"4202","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tumor-Extrinsic Axl Expression Shapes an Inflammatory Microenvironment Independent of Tumor Cell Promoting Axl Signaling in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"25","author":[{"given":"Kristina","family":"Breitenecker","sequence":"first","affiliation":[{"name":"Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Heiden","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Demmer","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Weber","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana-Maria","family":"Primorac","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viola","family":"Hedrich","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Ortmayr","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2671-0540","authenticated-orcid":false,"given":"Thomas","family":"Gruenberger","sequence":"additional","affiliation":[{"name":"Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, 1100 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Starlinger","sequence":"additional","affiliation":[{"name":"Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Centre of Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0987-0208","authenticated-orcid":false,"given":"Dietmar","family":"Herndler-Brandstetter","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0690-3473","authenticated-orcid":false,"given":"Iros","family":"Barozzi","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4612-7106","authenticated-orcid":false,"given":"Wolfgang","family":"Mikulits","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1002\/hep.27492","article-title":"Axl activates autocrine transforming growth factor-beta signaling in hepatocellular carcinoma","volume":"61","author":"Reichl","year":"2015","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/nrc3847","article-title":"The TAM family: Phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer","volume":"14","author":"Graham","year":"2014","journal-title":"Nat. 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