Myeloid-derived interleukin-1\u03b2 drives oncogenic KRAS-NF-\u03ba\u0392 addiction in malignant pleural effusion

Antonia Marazioti,Ioanna Giopanou,Dimitrios Kardamakis,Hara Apostolopoulou,Marianthi Iliopoulou,Georgia A Giotopoulou,Nikolaos I Kanellakis,Celestial Jones-Paris,Anthi C Krontira,Anastasios D Giannou,Theodora Agalioti,Timothy S Blackwell,Malamati Vreka,Argyro Kalogeropoulou,Yoichiro Iwakura,Stavros Taraviras,Magda Spella,Ioannis Lilis,Georgios T Stathopoulos

doi:10.1038/s41467-018-03051-z

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.

Highlights

Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers
The Nuclear factor (NF)-κBactivating kinases (ΙκΒ kinases, IKK) and pathways that mediate this oncogenic addiction between mutant KRAS and NF-κB signaling are still elusive and diverse, and different studies indicate that IKKα, IKKβ, IKKγ, IKKε, and/or TANK-binding kinase 1 (TBK1) are key for this[17,18,19,20,21,22,23,24]
KRAS mutant (MUT) cells displayed elevated DNA-binding activity of non-canonical NF-κB subunits P52 and RelB by functional NF-κΒ enzyme-linked immunosorbent assay (ELISA) and enhanced nuclear immunofluorescent localization of RelB compared with KRASWT cells (Fig. 1d, e)

Summary

Introduction

Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers. 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. 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. 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. IKKα is further shown to critically mediate IL-1β signaling in KRASmutant tumor cells, culminating in marked MPE-promoting effects delivered by C-X-C chemokine motif ligand 1 (CXCL1), and in oncogenic addiction with mutant KRAS evident as drug resistance. Simultaneous inhibition of IKKα and KRAS is effective in annihilating mutant KRAS-IKKα addiction in MPE

Methods

Results

Conclusion