Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma.

Autor:	Xu K; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany., Kessler A; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Department of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, Münster, Germany., Nichetti F; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.; Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Hoffmeister-Wittmann P; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Department of RadioOncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg, Germany., Scherr AL; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany., Nader L; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany., Kelmendi E; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany., Schmitt N; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany., Schwab M; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany., García-Beccaria M; Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.; Madrid Institute for Advanced Study (MIAS), Madrid, Spain., Sobol B; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany., Nieto OA; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany., Isele H; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany., Gärtner U; Interfaculty Biomedical Research Facility, University of Heidelberg, Heidelberg, Germany., Vaquero-Siguero N; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.; Cancer Progression and Metastasis Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Volk J; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.; Cancer Progression and Metastasis Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany., Korell F; German Cancer Consortium (DKTK), Heidelberg, Germany.; Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany., Mock A; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Institute for Pathology, Medical Faculty, Ludwig-Maximilians-University, Munich, Germany., Heide D; Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany., Ramadori P; Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany., Lenoir B; Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center, Heidelberg, Germany., Albrecht T; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Medical Faculty, Institute for Pathology, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany., Hüllein J; Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Jäger D; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany., Fröhling S; German Cancer Consortium (DKTK), Heidelberg, Germany.; Division of Translational Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Springfeld C; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany., Jackstadt R; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.; Cancer Progression and Metastasis Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany., Heikenwälder M; Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.; The M3 Research Center, Medical Faculty, University Clinic Tübingen (UKT), Tübingen, Germany., Dill MT; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Heidelberg, Germany.; Research Group Experimental Hepatology, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Roessler S; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Medical Faculty, Institute for Pathology, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany., Goeppert B; Institute of Pathology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany.; Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland., Köhler BC; Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	Liver international : official journal of the International Association for the Study of the Liver [Liver Int] 2024 Nov; Vol. 44 (11), pp. 2950-2963. Date of Electronic Publication: 2024 Aug 20.
DOI:	10.1111/liv.16069
Abstrakt:	Background and Aims: Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts with poor prognosis and limited treatment options. Prior evidence highlighted a significant contribution of the non-canonical NF-κB signalling pathway in initiation and aggressiveness of different tumour types. Lymphotoxin-β (LTβ) stimulates the NF-κB-inducing kinase (NIK), resulting in the activation of the transcription factor RelB. However, the functional contribution of the non-canonical NF-κB signalling pathway via the LTβ/NIK/RelB axis in CCA carcinogenesis and progression has not been established. Methods: Human CCA-derived cell lines and organoids were examined to determine the expression of NF-κB pathway components upon activation or inhibition. Proliferation and cell death were analysed using real-time impedance measurement and flow cytometry. Immunoblot, qRT-PCR, RNA sequencing and in situ hybridization were employed to analyse gene and protein expression. Four in vivo models of iCCA were used to probe the activation and regulation of the non-canonical NF-κB pathway. Results: Exposure to LTα1/β2 activates the LTβ/NIK/RelB axis and promotes proliferation in CCA. Inhibition of NIK with the small molecule inhibitor B022 efficiently suppresses RelB expression in patient-derived CCA organoids and nuclear co-translocation of RelB and p52 stimulated by LTα1/β2 in CCA cell lines. In murine CCA, RelB expression is significantly increased and LTβ is the predominant ligand of the non-canonical NF-κB signalling pathway. Conclusions: Our study confirms that the non-canonical NF-κB axis LTβ/NIK/RelB drives cholangiocarcinogenesis and represents a candidate therapeutic target. (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)
Databáze:	MEDLINE
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