Direct Reprogramming of Hepatocytes Into JAK/Stat-Dependent LGR5+ Liver Cells Able to Initiate Intrahepatic Cholangiocarcinoma

Author:

Chaker Diana12,Desterke Christophe13,Moniaux Nicolas34,Bani Mohamed-Amine56,Oudrhiri Noufissa127,Faivre Jamila347,Turhan Ali G12378,Bennaceur-Griscelli Annelise1237,Griscelli Frank1259ORCID

Affiliation:

1. Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 1310, Université Paris Saclay , Villejuif , France

2. Institut National de la Santé et de la Recherche Médicale (INSERM) UMS 045 - CITHERA “Center for iPSC Cell Therapy,” Genopole, National Infrastructure INGESTEM , Corbeil-Essonnes, Evry. France

3. Université Paris-Saclay, Faculté de Médecine Kremlin Bicêtre , France

4. Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS1193 , Villejuif , France

5. Institut Gustave-Roussy, Département de Biologie et Pathologie Médicale, service de pathologie morphologique , Villejuif , France

6. Gustave Roussy Cancer Centre, Université Paris-Saclay, Inserm US23 , CNRS, AMMICa, Villejuif , France

7. Service d’Hématologie Biologique Laboratoire d’Onco-Hematologie moleculaire et Cytogénetique APHP, Hôpital Universitaire Paris Sud Paul-Brousse , Villejuif , France

8. Service d’Hématologie Biologique, Hôpital Universitaire Paris Sud , (AP-HP) 94 Kremlin Bicêtre , France

9. Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques , Paris , France

Abstract

Abstract 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 Δ1Δ3-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/β-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.

Funder

National Infrastructure Program

Inserm, University Paris Saclay

Publisher

Oxford University Press (OUP)

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