Journal Article

DKFZ-2024-01701

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma.

Xu, K. ; Kessler, A. ; Nichetti, F. (First author)DKFZ* ; Hoffmeister-Wittmann, P. ; Scherr, A.-L. ; Nader, L. ; Kelmendi, E. ; Schmitt, N. ; Schwab, M. ; García-Beccaria, M.DKFZ* ; Sobol, B. ; Nieto, O. A. ; Isele, H. ; Gärtner, U. ; Vaquero-Siguero, N.DKFZ* ; Volk, J.DKFZ* ; Korell, F.DKFZ* ; Mock, A.DKFZ* ; Heide, D.DKFZ* ; Ramadori, P.DKFZ* ; Lenoir, B.DKFZ* ; Albrecht, T. ; Hüllein, J.DKFZ* ; Jäger, D.DKFZ* ; Fröhling, S.DKFZ* ; Springfeld, C. ; Jackstadt, R.-F.DKFZ* ; Heikenwälder, M.DKFZ* ; Dill, M.DKFZ* ; Roessler, S. ; Goeppert, B. ; Köhler, B. C.DKFZ*

2024
Wiley-Blackwell Oxford

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Please use a persistent id in citations: doi:10.1111/liv.16069

Abstract: 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.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.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.Our study confirms that the non-canonical NF-κB axis LTβ/NIK/RelB drives cholangiocarcinogenesis and represents a candidate therapeutic target.

Keyword(s): LTB ; NF‐κB ; NIK ; RelB ; cholangiocarcinoma ; small molecule inhibitor B022

Note: #EA:B340# / 2024 Nov;44(11):2950-2963 / DKFZ-ZMBH Alliance

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Contributing Institute(s):

1. Translationale Medizinische Onkologie (B340)
2. Chronische Entzündung und Krebs (D440)
3. NWG Tumorprogression und Metastasierung (A013)
4. NWG Experimentelle Hepatologie, Entzündung und Krebs (D500)
5. DKTK HD zentral (HD01)
6. Angewandte Tumor-Immunität (D120)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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