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

Antonia Marazioti (), Ioannis Lilis, Malamati Vreka, Hara Apostolopoulou, Argyro Kalogeropoulou, Ioanna Giopanou, Georgia A. Giotopoulou, Anthi C. Krontira, Marianthi Iliopoulou, Nikolaos I. Kanellakis, Theodora Agalioti, Anastasios D. Giannou, Celestial Jones-Paris, Yoichiro Iwakura, Dimitrios Kardamakis, Timothy S. Blackwell, Stavros Taraviras, Magda Spella and Georgios T. Stathopoulos ()
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Antonia Marazioti: University of Patras
Ioannis Lilis: University of Patras
Malamati Vreka: University of Patras
Hara Apostolopoulou: University of Patras
Argyro Kalogeropoulou: University of Patras
Ioanna Giopanou: University of Patras
Georgia A. Giotopoulou: University of Patras
Anthi C. Krontira: University of Patras
Marianthi Iliopoulou: University of Patras
Nikolaos I. Kanellakis: University of Patras
Theodora Agalioti: University of Patras
Anastasios D. Giannou: University of Patras
Celestial Jones-Paris: Vanderbilt University School of Medicine
Yoichiro Iwakura: Tokyo University of Science
Dimitrios Kardamakis: University of Patras
Timothy S. Blackwell: Vanderbilt University School of Medicine
Stavros Taraviras: University of Patras
Magda Spella: University of Patras
Georgios T. Stathopoulos: University of Patras

Nature Communications, 2018, vol. 9, issue 1, 1-16

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

Date: 2018
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DOI: 10.1038/s41467-018-03051-z

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