2. Academic Validation
  3. Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma

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

  • Liver Int. 2024 Aug 20. doi: 10.1111/liv.16069.
Kaiyu Xu 1 2 3,  Annika Kessler 1 2 4,  Federico Nichetti 5 6,  Paula Hoffmeister-Wittmann 1 2 7,  Anna-Lena Scherr 1 2,  Luisa Nader 1 2,  Eblina Kelmendi 1 2,  Nathalie Schmitt 1 2,  Maximilian Schwab 1 2,  María García-Beccaria 8 9,  Benjamin Sobol 1 10,  Osama Azzam Nieto 1 10,  Hanna Isele 1 2 3,  Ulrike Gärtner 11,  Nuria Vaquero-Siguero 12 13 14,  Julia Volk 3 12 13,  Felix Korell 15 16,  Andreas Mock 1 15 17 18,  Danijela Heide 8,  Pierluigi Ramadori 8,  Bénédicte Lenoir 19,  Thomas Albrecht 2 20,  Jennifer Hüllein 6,  Dirk Jäger 1 2,  Stefan Fröhling 15 21 22 23,  Christoph Springfeld 1 2,  Rene Jackstadt 12 13,  Mathias Heikenwälder 8 24,  Michael T Dill 2 25 26,  Stephanie Roessler 2 20,  Benjamin Goeppert 27 28,  Bruno C Köhler 1 2 15
Affiliations

Affiliations

  • 1 Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.
  • 2 Liver Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.
  • 3 Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
  • 4 Department of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, Münster, Germany.
  • 5 Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
  • 6 Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 7 Department of RadioOncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg, Germany.
  • 8 Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.
  • 9 Madrid Institute for Advanced Study (MIAS), Madrid, Spain.
  • 10 Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany.
  • 11 Interfaculty Biomedical Research Facility, University of Heidelberg, Heidelberg, Germany.
  • 12 Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
  • 13 Cancer Progression and Metastasis Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
  • 14 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 15 German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 16 Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
  • 17 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 18 Institute for Pathology, Medical Faculty, Ludwig-Maximilians-University, Munich, Germany.
  • 19 Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center, Heidelberg, Germany.
  • 20 Medical Faculty, Institute for Pathology, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany.
  • 21 Division of Translational Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 22 National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
  • 23 Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
  • 24 The M3 Research Center, Medical Faculty, University Clinic Tübingen (UKT), Tübingen, Germany.
  • 25 Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Heidelberg, Germany.
  • 26 Research Group Experimental Hepatology, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 27 Institute of Pathology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany.
  • 28 Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland.
PMID: 39164890 DOI: 10.1111/liv.16069
Abstract

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.

Keywords

LTB; NF‐κB; NIK; RelB; cholangiocarcinoma; small molecule inhibitor B022.

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