{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T17:15:16Z","timestamp":1778260516801,"version":"3.51.4"},"reference-count":37,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Molecular mechanisms responsible for the poor prognosis in patients with intrahepatic cholangiocarcinoma (CCA) are still unknown, but stem cell marker Cluster Differentiation 90 (CD90) has been reported to be associated with a more aggressive cancer phenotype. In this scenario, the TGF-\u03b21 signaling pathway likely has a role as master gene regulator. Aim of the study is to investigate the role of CD90 in iCCA aggressiveness. The molecular profile of HuCCT1\/CD90+ and HuCCT1\/CD90\u2212 cells was obtained through transcriptomic analysis (NGS). Bioinformatic data were confirmed in both cell lines by qRT-PCR and Western blot. Cells were treated with Gemcitabine in monotherapy or in combination with Galunisertib, a selective inhibitor of TGF-\u03b2RI, in 2D and 3D models. HuCCT1\/CD90+ cells are more proliferative, less migratory, and resistant to Gemcitabine treatment. HuCCT1\/CD90+ cells also express lower levels of TGF-\u03b21 compared to \/CD90\u2212 cell lines. Finally, HuCCT1\/CD90+ cells are resistant to Gemcitabine, while the combination of Gemcitabine and Galunisertib displays a synergistic effect on HuCCT1\/CD90+ cell proliferation. These results underline that CD90-induced Gemcitabine resistance can be overcome by adding a TGF\u03b21 inhibitor such as Galunisertib, thereby moving further toward a precision medicine approach in patients with iCCA.<\/jats:p>","DOI":"10.3390\/ijms26114973","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T07:04:28Z","timestamp":1747897468000},"page":"4973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibiting the TGF-\u03b21 Pathway Reduces the Aggressiveness of Intrahepatic CCA HuCCT1 CD90-Positive Cells"],"prefix":"10.3390","volume":"26","author":[{"given":"Elena","family":"Pizzuto","sequence":"first","affiliation":[{"name":"Personalized Medicine Laboratory, National Institute of Gastroenterology \u201cS. de Bellis\u201d IRCCS Research Hospital, 70013 Castellana Grotte, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2692-1169","authenticated-orcid":false,"given":"Serena","family":"Mancarella","sequence":"additional","affiliation":[{"name":"Personalized Medicine Laboratory, National Institute of Gastroenterology \u201cS. de Bellis\u201d IRCCS Research Hospital, 70013 Castellana Grotte, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3712-4149","authenticated-orcid":false,"given":"Isabella","family":"Gigante","sequence":"additional","affiliation":[{"name":"Personalized Medicine Laboratory, National Institute of Gastroenterology \u201cS. de Bellis\u201d IRCCS Research Hospital, 70013 Castellana Grotte, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2971-0802","authenticated-orcid":false,"given":"Grazia","family":"Serino","sequence":"additional","affiliation":[{"name":"Personalized Medicine Laboratory, National Institute of Gastroenterology \u201cS. de Bellis\u201d IRCCS Research Hospital, 70013 Castellana Grotte, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Dituri","sequence":"additional","affiliation":[{"name":"Personalized Medicine Laboratory, National Institute of Gastroenterology \u201cS. de Bellis\u201d IRCCS Research Hospital, 70013 Castellana Grotte, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7988-1917","authenticated-orcid":false,"given":"Emanuele","family":"Piccinno","sequence":"additional","affiliation":[{"name":"Personalized Medicine Laboratory, National Institute of Gastroenterology \u201cS. de Bellis\u201d IRCCS Research Hospital, 70013 Castellana Grotte, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0136-8440","authenticated-orcid":false,"given":"Isabel","family":"Fabregat","sequence":"additional","affiliation":[{"name":"TGF-\u03b2 and Cancer Group\u2014Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08860 L\u2019Hospitalet de Llobregat, Spain"},{"name":"National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5140-8060","authenticated-orcid":false,"given":"Gianluigi","family":"Giannelli","sequence":"additional","affiliation":[{"name":"Personalized Medicine Laboratory, National Institute of Gastroenterology \u201cS. de Bellis\u201d IRCCS Research Hospital, 70013 Castellana Grotte, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/bs.acr.2020.10.005","article-title":"Intrahepatic Cholangiocarcinoma: Morpho-Molecular Pathology, Tumor Reactive Microenvironment, and Malignant Progression","volume":"Volume 149","author":"Sirica","year":"2021","journal-title":"Advances in Cancer Research"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"198","DOI":"10.3322\/caac.21759","article-title":"Advances in the Treatment of Intrahepatic Cholangiocarcinoma: An Overview of the Current and Future Therapeutic Landscape for Clinicians","volume":"73","author":"Moris","year":"2023","journal-title":"CA Cancer J. 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