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http://hdl.handle.net/10889/11464
Title: | Myeloid-derived interleukin-1β drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion |
Authors: | 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 |
Keywords: | Malignant pleural effusion KRAS mutations Mutant KRAS facilitates IKKα-mediated responsiveness |
Keywords (translated): | Κακοήθης υπεζωκοτική συλλογή Μεταλλάξεις KRAS |
Source: | Nature ommunications |
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. |
Abstract (translated): | - |
Appears in Collections: | Τμήμα Ιατρικής (Δημοσ. Π.Π. σε περιοδικά) |
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