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Spella, M. ; Ntaliarda, G. ; Skiadas, G. ; Lamort, A.-S. ; Vreka, M. ; Marazioti, A. ; Lilis, I. ; Bouloukou, E. ; Giotopoulou, G.A. ; Pepe, M. ; Weiss, S.A. ; Petrera, A. ; Hauck, S.M. ; Koch, I.* ; Lindner, M.* ; Hatz, R.A.* ; Behr, J.* ; Arendt, K.A.M. ; Giopanou, I. ; Brunn, D.* ; Savai, R.* ; Jenne, D. ; de Château, M.* ; Yull, F.E.* ; Blackwell, T.S.* ; Stathopoulos, G.T.

Non-oncogene addiction of KRAS-mutant cancers to IL-1β via versican and mononuclear IKKβ.

Cancers 15:23 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β. Human pan-cancer and experimental NF-κB reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKKβ activation and IL-1β release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKβ deletion prevents myeloid NF-κB activation and metastasis. Versican and IKKβ are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1β addiction is abolished by IL-1β and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKβ in metastasis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Bioluminescence ; Cancer ; Inflammation ; Interleukin-1β ; Non-oncogene Addiction ; Nuclear Factor-κb; Kappa-b Activation; Mouse Model; Mast-cells; T-cells; Lung; Immune; Mice; Inflammation; Antagonist; Inhibitors
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 2072-6694
Journal Cancers
Quellenangaben Volume: 15, Issue: 6, Pages: , Article Number: 23 Supplement: ,
Publisher MDPI
Publishing Place St Alban-anlage 66, Ch-4052 Basel, Switzerland
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
CF Metabolomics & Proteomics (CF-MPC)
POF-Topic(s) 30202 - Environmental Health
30203 - Molecular Targets and Therapies
Research field(s) Lung Research

Enabling and Novel Technologies
PSP Element(s) G-501600-003
G-501600-001
G-501600-005
A-630700-001
G-505700-001
Grants Deutsches Zentrum fur Lungenforschung
Bundesministerium fur Bildung und Forschung grant ALTERNATIVE
Deutsche Forschungsgemeinschaft Graduiertenkolleg
European Research Council 2015 Proof of Concept grant
European Research Council 2010 Starting Independent Investigator grant
Department of Veteran Affairs
National Institutes of Health
Buzzard Pharmaceuticals
Hellenic Foundation for Research and Innovation
General Secretariat for Research and Innovation
DOI 10.3390/cancers15061866
WOS ID 000968443900001
Scopus ID 85151413428
PubMed ID 36980752
Erfassungsdatum 2023-10-06
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