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