Science and Research

Myeloid-derived interleukin-1beta drives oncogenic KRAS-NF-kappaBeta addiction in malignant pleural effusion

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 IKKalpha-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1beta. Indeed, IKKalpha is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-kappaB signaling. IL-1beta fuels addiction of mutant KRAS to IKKalpha resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1beta-mediated NF-kappaB induction in KRAS-mutant tumor cells, as well as their resulting MPE-competence, can only be blocked by co-inhibition of both KRAS and IKKalpha, a strategy that overcomes drug resistance to individual treatments. Hence we show that mutant KRAS facilitates IKKalpha-mediated responsiveness of tumor cells to host IL-1beta, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance.

  • 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.

Keywords

  • Animals
  • Cell Line, Tumor
  • Chemokine CXCL1/metabolism
  • Female
  • *Genes, ras
  • Humans
  • I-kappa B Kinase/metabolism
  • Interleukin-1beta/*metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Myeloid Cells/*metabolism
  • NF-kappa B/*metabolism
  • Pleural Effusion, Malignant/*metabolism
  • Receptors, Interleukin-1/metabolism
Publication details
DOI: 10.1038/s41467-018-03051-z
Journal: Nature communications
Pages: 672 
Number: 1
Work Type: Original
Location: CPC-M
Disease Area: LC
Partner / Member: LMU
Access-Number: 29445180
See publication on PubMed

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