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

• Κύριοι συγγραφείς: Marazioti, Antonia, Lilis, Ioannis, Vreka, Malamati, Apostolopoulou, Hara, Kalogeropoulou, Argyro, Giopanou, Ioanna, Giotopoulou, Georgia, Krontira, Anthi, Iliopoulou, Marianthi, Kanellakis, Nikolaos, Agalioti, Theodora, Giannou, Anastasios, Jones-Paris, Celestial, Iwakura, Yoichiro, Kardamakis, Dimitrios, Blackwell, Timothy, Taraviras, Stavros, Spella, Magda, Stathopoulos, Georgios
• Άλλοι συγγραφείς: Μαραζιώτη, Αντωνία
• Μορφή: Journal (paper)
• Γλώσσα: English
• Έκδοση: 2018
• Θέματα: Malignant pleural effusion; KRAS mutations; Mutant KRAS facilitates; IKKα-mediated responsiveness; Κακοήθης υπεζωκοτική συλλογή; Μεταλλάξεις KRAS

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.