IRAK-M expression in tumor cells supports colorectal cancer progression through reduction of antimicrobial defence and cell intrinsic stabilisation of STAT3

The intestinal tract in steady state is in a condition of homeostasis characterized by a balanced interaction of the microbiome and the mucosal immune system, which has to be tightly regulated to prevent inflammation. Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity and tumor-associated inflammation. An important regulator for maintaining intestinal homeostasis is IRAK-M, a negative regulator of TLR signalling. In this study, we investigated the impact of IRAK-M on colorectal cancerogenesis. We showed that TLR signalling and Wnt activation induce IRAK-M expression in tumor cells. IRAK-M is responsible for regulation of microbial colonization and STAT3 stability in tumor cells leading to progression of CRC. IRAK-M expression in human CRC is associated with poor prognosis predisposing IRAK-M as an therapeutic target.