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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)

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	Open Access Gold

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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

Corresponding Author

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

ISSN (print) / ISBN 2072-6694

Journal Cancers

Quellenangaben Volume: 15, Issue: 6, Article Number: 23

Publisher MDPI

Publishing Place St Alban-anlage 66, Ch-4052 Basel, Switzerland

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Lung Health and Immunity (LHI)
CF Metabolomics & Proteomics (CF-MPC)

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