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Marazioti, A.* ; Lilis, I.* ; Vreka, M. ; Apostolopoulou, H.* ; Kalogeropoulou, A.* ; Giopanou, I.* ; Giotopoulou, G.A.* ; Krontira, A.C.* ; Iliopoulou, M.* ; Kanellakis, N.I.* ; Agalioti, T.* ; Giannou, A.D.* ; Jones-Paris, C.* ; Iwakura, Y.* ; Kardamakis, D.* ; Blackwell, T.S.* ; Taraviras, S.* ; Spella, M.* ; Stathopoulos, G.T.

Myeloid-derived interleukin-1β drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion.

Nat. Commun. 9:672 (2018)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers. While we previously identified KRAS mutations as molecular culprits of MPE formation, the underlying mechanism remained unknown. Here, we determine that non-canonical IKK alpha-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1 beta. Indeed, IKK alpha is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-kappa B signaling. IL-1 beta fuels addiction of mutant KRAS to IKK alpha resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1 beta-mediated NF-kappa B induction in KRAS-mutant tumor cells, as well as their resulting MPE-competence, can only be blocked by co-inhibition of both KRAS and IKK alpha, a strategy that overcomes drug resistance to individual treatments. Hence we show that mutant KRAS facilitates IKK alpha-mediated responsiveness of tumor cells to host IL-1 beta, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Squamous-cell Carcinoma; Tumor-necrosis-factor; Lung-cancer; B Activation; Ikk-alpha; Gene-expression; Mouse Model; Ras; Adenocarcinoma; Inhibition
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 9, Issue: 1, Pages: , Article Number: 672 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)