Probes for INS

Constitutive 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 pro-inflammatory 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 β-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. Additionally, Ikkε was also required for lipopolysaccharide (LPS) and IL-17A-induced activation of Akt, Mek1/2, Erk1/2 and Msk1. Accordingly, genes encoding pro-inflammatory cytokines, chemokines and anti-microbial peptides were downregulated in Ikkε-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL-17A synthesis. Further studies revealed that IL-17A 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 IL-17A-dependent signaling pathways converge on Ikkε to promote cell survival and establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation.βε.