TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.

Journal of Hepatology
Benjamin J DwyerStuart J Forbes

Abstract

Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA. The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis. Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing ...Continue Reading

References

May 1, 2002·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Donna M DambachDebra L Laskin
Nov 26, 2002·Biochemical and Biophysical Research Communications·Norihiro HaradaKo Okumura
May 18, 2004·Biochemical and Biophysical Research Communications·Tomoyuki KawakitaTakeshi Nakano
Aug 20, 2005·The Journal of Clinical Investigation·Aniela JakubowskiLinda C Burkly
Jul 31, 2007·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Ahmed M Elsharkawy, Derek A Mann
Jun 26, 2009·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Karlin Raja KarlmarkFrank Tacke
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Sayaka InokuchiEkihiro Seki
Jun 26, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Janina E E Tirnitz-ParkerBelinda Knight
Jul 20, 2010·Clinical and Experimental Immunology·C SubimerbS Wongkham
Nov 1, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Christian D FingasGregory J Gores
Feb 18, 2012·International Journal of Cancer. Journal International Du Cancer·Hirohisa OkabeHideo Baba
Jul 17, 2012·The Journal of Clinical Investigation·Biao FanHolger Willenbring
Oct 2, 2012·The Journal of Clinical Investigation·Sayaka Sekiya, Atsushi Suzuki
Mar 19, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Massimiliano CadamuroMario Strazzabosco
Apr 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Thomas G BirdStuart J Forbes
Dec 7, 2013·Cancer Research·Rachel V GuestStuart J Forbes
Feb 20, 2014·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Watcharin LoilomeGregory J Riggins
Jul 30, 2014·Gastroenterology·Fabio Marra, Frank Tacke
Nov 13, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ulrik N LassenGlenwood D Goss
Feb 18, 2015·The Journal of Clinical Investigation·Luke BoulterStuart J Forbes
Oct 9, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Didier MeulendijksJan H M Schellens
Oct 30, 2016·Proceedings of the National Academy of Sciences of the United States of America·Rachel V GuestStuart J Forbes
Jan 19, 2017·International Journal of Molecular Sciences·Massimiliano CadamuroLuca Fabris
Oct 11, 2017·Nature Reviews. Clinical Oncology·Sumera RizviGregory J Gores
May 24, 2020·Annals of the New York Academy of Sciences·Martha Lopez-YrigoyenJeffrey W Pollard
Jul 2, 2020·Nature Reviews. Gastroenterology & Hepatology·Jesus M BanalesGregory J Gores

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Citations

Jan 30, 2021·Expert Opinion on Investigational Drugs·Scott H Waddell, Luke Boulter
Feb 5, 2021·The International Journal of Biochemistry & Cell Biology·Francis D GratteJanina E E Tirnitz-Parker
Feb 23, 2021·Journal of Hepatology·Raffaella Casolino, Chiara Braconi

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