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Vucur, M.* ; Ghallab, A.* ; Schneider, A.T.* ; Adili, A.* ; Cheng, M.* ; Castoldi, M.* ; Singer, M.T.* ; Büttner, V.* ; Keysberg, L.S.* ; Küsgens, L.* ; Kohlhepp, M.* ; Görg, B.* ; Gallage, S.* ; Barragan Avila, J.E.* ; Unger, K. ; Kordes, C.* ; Leblond, A.L.* ; Albrecht, W.* ; Loosen, S.H.* ; Lohr, C.* ; Jördens, M.S.* ; Babler, A.* ; Hayat, S.* ; Schumacher, D.* ; Koenen, M.T.* ; Govaere, O.* ; Boekschoten, M.V.* ; Jors, S.* ; Villacorta-Martin, C.* ; Mazzaferro, V.* ; Llovet, J.M.* ; Weiskirchen, R.* ; Kather, J.N.* ; Starlinger, P.* ; Trauner, M.* ; Luedde, M.* ; Heij, L.R.* ; Neumann, U.P.* ; Keitel, V.* ; Bode, J.G.* ; Schneider, R.K.* ; Tacke, F.* ; Levkau, B.* ; Lammers, T.* ; Fluegen, G.* ; Alexandrov, T.* ; Collins, A.L.* ; Nelson, G.* ; Oakley, F.* ; Mann, D.A.* ; Roderburg, C.* ; Longerich, T.* ; Weber, A.* ; Villanueva, A.* ; Samson, A.L.* ; Murphy, J.M.* ; Kramann, R.* ; Geisler, F.* ; Costa, I.G.* ; Hengstler, J.G.* ; Heikenwälder, M.* ; Luedde, T.*

Sublethal necroptosis signaling promotes inflammation and liver cancer.

Immunity 56, 1578-1595.e8 (2023)
Publ. Version/Full Text DOI PMC
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It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged “sublethal” state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hcc ; Intravital Imaging ; Mlkl ; Nf-κb ; Rip1 ; Rip3 ; Ripk1 ; Ripk3 ; Traf2 ; Undead Cells; Nf-kappa-b; Gene-expression Signature; Cell-death; Hepatocellular-carcinoma; Mouse Hepatocytes; Activation; Traf2; Rip3; Tak1; Hepatocarcinogenesis
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 1074-7613
e-ISSN 1097-4180
Journal Immunity
Quellenangaben Volume: 56, Issue: 7, Pages: 1578-1595.e8 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Translational Metabolic Oncology (IDC-TMO)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Radiation Sciences
PSP Element(s) G-501000-001
Grants Cancer Research UK
DOI 10.1016/j.immuni.2023.05.017
WOS ID 001051374800001
Scopus ID 85164427177
PubMed ID 37329888
Erfassungsdatum 2023-10-18
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