{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:42:44Z","timestamp":1787726564635,"version":"build-2784847793"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T00:00:00Z","timestamp":1705968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"National Infrastructure Program","award":["ANR-11-INBS-0009-INGESTEM"],"award-info":[{"award-number":["ANR-11-INBS-0009-INGESTEM"]}]},{"name":"Inserm, University Paris Saclay"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Somatic cells that have been partially reprogrammed by the factors Oct4, Sox2, Klf4, and cMyc (OSKM) have been demonstrated to be potentially tumorigenic in vitro and in vivo due to the acquisition of cancer-associated genomic alterations and the absence of OSKM clearance over time. In the present study, we obtained partially reprogrammed, SSEA1-negative cells by transducing murine hepatocytes with \u03941\u03943-deleted adenoviruses that expressed the 4 OSKM factors. We observed that, under long-term 2D and 3D culture conditions, hepatocytes could be converted into LGR5-positive cells with self-renewal capacity that was dependent on 3 cross-signaling pathways: IL6\/Jak\/Stat3, LGR5\/R-spondin, and Wnt\/\u03b2-catenin. Following engraftment in syngeneic mice, LGR5-positive cells that expressed the cancer markers CD51, CD166, and CD73 were capable of forming invasive and metastatic tumors reminiscent of intrahepatic cholangiocarcinoma (ICC): they were positive for CK19 and CK7, featured associations of cord-like structures, and contained cuboidal and atypical cells with dissimilar degrees of pleomorphism and mitosis. The LGR5+-derived tumors exhibited a highly vascularized stroma with substantial fibrosis. In addition, we identified pro-angiogenic factors and signaling pathways involved in neo-angiogenesis and vascular development, which represent potential new targets for anti-angiogenic strategies to overcome tumor resistance to current ICC treatments.<\/jats:p>","DOI":"10.1093\/stmcls\/sxae006","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T12:34:41Z","timestamp":1705926881000},"page":"301-316","source":"Crossref","is-referenced-by-count":5,"title":["Direct Reprogramming of Hepatocytes Into JAK\/Stat-Dependent LGR5+ Liver Cells Able to Initiate Intrahepatic Cholangiocarcinoma"],"prefix":"10.1093","volume":"42","author":[{"given":"Diana","family":"Chaker","sequence":"first","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMRS 1310, Universit\u00e9 Paris Saclay , Villejuif , France"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMS 045 - CITHERA \u201cCenter for iPSC Cell Therapy,\u201d Genopole, National Infrastructure INGESTEM , Corbeil-Essonnes, Evry. France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Desterke","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMRS 1310, Universit\u00e9 Paris Saclay , Villejuif , France"},{"name":"Universit\u00e9 Paris-Saclay, Facult\u00e9 de M\u00e9decine Kremlin Bic\u00eatre , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Moniaux","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Facult\u00e9 de M\u00e9decine Kremlin Bic\u00eatre , France"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMRS1193 , Villejuif , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed-Amine","family":"Bani","sequence":"additional","affiliation":[{"name":"Institut Gustave-Roussy, D\u00e9partement de Biologie et Pathologie M\u00e9dicale, service de pathologie morphologique , Villejuif , France"},{"name":"Gustave Roussy Cancer Centre, Universit\u00e9 Paris-Saclay, Inserm US23 , CNRS, AMMICa, Villejuif , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noufissa","family":"Oudrhiri","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMRS 1310, Universit\u00e9 Paris Saclay , Villejuif , France"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMS 045 - CITHERA \u201cCenter for iPSC Cell Therapy,\u201d Genopole, National Infrastructure INGESTEM , Corbeil-Essonnes, Evry. France"},{"name":"Service d\u2019H\u00e9matologie Biologique Laboratoire d\u2019Onco-Hematologie moleculaire et Cytog\u00e9netique APHP, H\u00f4pital Universitaire Paris Sud Paul-Brousse , Villejuif , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamila","family":"Faivre","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Facult\u00e9 de M\u00e9decine Kremlin Bic\u00eatre , France"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMRS1193 , Villejuif , France"},{"name":"Service d\u2019H\u00e9matologie Biologique Laboratoire d\u2019Onco-Hematologie moleculaire et Cytog\u00e9netique APHP, H\u00f4pital Universitaire Paris Sud Paul-Brousse , Villejuif , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali G","family":"Turhan","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMRS 1310, Universit\u00e9 Paris Saclay , Villejuif , France"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMS 045 - CITHERA \u201cCenter for iPSC Cell Therapy,\u201d Genopole, National Infrastructure INGESTEM , Corbeil-Essonnes, Evry. France"},{"name":"Universit\u00e9 Paris-Saclay, Facult\u00e9 de M\u00e9decine Kremlin Bic\u00eatre , France"},{"name":"Service d\u2019H\u00e9matologie Biologique Laboratoire d\u2019Onco-Hematologie moleculaire et Cytog\u00e9netique APHP, H\u00f4pital Universitaire Paris Sud Paul-Brousse , Villejuif , France"},{"name":"Service d\u2019H\u00e9matologie Biologique, H\u00f4pital Universitaire Paris Sud , (AP-HP) 94 Kremlin Bic\u00eatre , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelise","family":"Bennaceur-Griscelli","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMRS 1310, Universit\u00e9 Paris Saclay , Villejuif , France"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMS 045 - CITHERA \u201cCenter for iPSC Cell Therapy,\u201d Genopole, National Infrastructure INGESTEM , Corbeil-Essonnes, Evry. France"},{"name":"Universit\u00e9 Paris-Saclay, Facult\u00e9 de M\u00e9decine Kremlin Bic\u00eatre , France"},{"name":"Service d\u2019H\u00e9matologie Biologique Laboratoire d\u2019Onco-Hematologie moleculaire et Cytog\u00e9netique APHP, H\u00f4pital Universitaire Paris Sud Paul-Brousse , Villejuif , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0318-2754","authenticated-orcid":false,"given":"Frank","family":"Griscelli","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMRS 1310, Universit\u00e9 Paris Saclay , Villejuif , France"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMS 045 - CITHERA \u201cCenter for iPSC Cell Therapy,\u201d Genopole, National Infrastructure INGESTEM , Corbeil-Essonnes, Evry. 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