Göktuna, S. I.Shostak, K.Chau, T.-L.Heukamp, L.C.Hennuy, B.Duong, H.-Q.Ladang, A.Close, P.Klevernic, I.Olivier, F.Florin, A.Ehx, G.Baron, F.Vandereyken, M.Rahmouni, S.Vereecke, L.Loo, G. V.Büttner, R.Greten, F. R.Chariot, A.2018-04-122018-04-122016-050008-5472http://hdl.handle.net/11693/37175Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkϵ in Wnt-driven tumor development. We found that Ikkϵ was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkϵ in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkϵ to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkϵ was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkϵ-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkϵ phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkϵ to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation.EnglishBeta cateninI kappa B kinase epsilonImmunoglobulin enhancer binding proteinInterleukin 17LipopolysaccharideMitogen activated protein kinase 1Mitogen activated protein kinase 3Mitogen activated protein kinase kinase 1Mitogen activated protein kinase kinase 2Protein kinase BStress activated protein kinase 1Wnt proteinI kappa B kinaseInterleukin 17LipopolysaccharideWnt proteinAnimal cellAnimal experimentAnimal modelAnimal tissueApoptosisArticleCancer growthCancer incidenceCancer survivalControlled studyIntestine cancerIntestine epithelium cellMouseNonhumanPositive feedbackPriority journalProtein expressionProtein functionProtein phosphorylationSignal transductionTumor associated leukocyteTumor microenvironmentTumor promotionAnimalDisease modelFlow cytometryHumanImmunoprecipitationIn situ hybridizationIntestine tumorMetabolismPathologyPhysiologyReal time polymerase chain reactionTransgenic mouseTumor cell lineAnimalsCell Line, TumorDisease Models, AnimalFlow CytometryHumansI-kappa B KinaseImmunoprecipitationIn Situ HybridizationInterleukin-17Intestinal NeoplasmsLipopolysaccharidesMiceMice, TransgenicReal-Time Polymerase Chain ReactionSignal TransductionTumor MicroenvironmentWnt ProteinsArticle10.1158/0008-5472.CAN-15-1473