• Dr. Göktuna’s article has been published in the Cancer Research

Abstract

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-promoting environment has not been extensively studied. Therefore, we assessed the relationship between the pro-inflammatory Ikk-related kinase, Ikkepsilon, in Wnt-driven tumor development. We found that Ikkepsilon was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkepsilon in APC or β-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkepsilon to limited TNF-dependent apoptosis using transformed intestinal epithelial cells. Additionally, Ikkepsilon 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, including IL-17A, were downregulated in Ikkepsilon-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages. Further studies revealed that IL-17A synergized with commensal bacteria to trigger Ikkepsilon 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 Ikkepsilon to promote cell survival and establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation.