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Background Colorectal cancer (CRC) is the 2nd leading cause of cancer death in Canada. A major risk factor for this disease is chronic inflammation. Despite the clear link between inflammation and cancer, the exact mechanism by which colitis leads to cancer is unknown. Our group has previously shown that a rare cell type in the gut marked by the expression of doublecortin-like kinase-1 (Dclk1) and known as a tuft cell, is quiescent, long-lived, and resistant to proliferation even upon mutation of the tumor suppressor APC. Interestingly, in the setting of colitis, these APC-mutated tuft cells become powerful cancer-initiating cells, but the mechanism by which this occurs is not known. NF-kB signaling is a major inflammatory pathway active in colitis and that has been linked to colorectal cancer. Inhibition of the NF-kB pathway in intestinal epithelial cells has also been shown to inhibit tumor initiation in a mouse model of colitis-associated cancer (Greten et al., 2004). Aims In the present study, we aim to examine the effect of NF-kB inhibition in tuft cells on colitis-associated cancer. Methods Dclk1CreERT2/APCf/f mice were crossed to IKK-β f/f mice and administered tamoxifen to conditionally knockout the function of both APC and IKK-β in tuft cells. Mice were then exposed to the colitis-inducing agent dextran sodium sulfate (DSS) to induce tumorigenesis. Approximately 16 weeks post-tamoxifen, colonic tumor number and size were analyzed to determine the effect of NF-kB pathway inhibition on tumor initiation and growth, respectively. Extent of inflammation was assessed by myeloperoxidase (MPO) activity and histological damage, and colonic tissue was collected for measurement of inflammatory mediators by qRT-PCR at both acute and long-term time points. Results Interestingly, at baseline we detected increased MPO activity in Dclk1CreERT2/APCf/f/IKK-β f/f mice compared to control mice, suggesting that inhibition of NF-kB in Dclk1+ cells may increase basal colonic inflammation. Consistent with this observation, inhibition of the NF-kB pathway also resulted in an increased number of tuft cell-derived tumors, with no observed change in tumor size. Acutely, we also observed an exacerbation of DSS-colitis in Dclk1CreERT2/APCf/f/IKK-β f/f mice, as detected by elevated MPO activity, increased histological damage, and reduced colon length compared to wildtype (IKK-β +/+) controls. Conclusions These data suggest that Dclk1+ cell-specific NF-kB signaling plays a key protective role against colitis and colitis-associated tumorigenesis. Targeting the NF-kB pathway may reduce the severity of colitis and the incidence of colitis-associated cancer. Funding Agencies CIHR

A30 INHIBITION OF NF-KB SIGNALING IN DCLK1+ CELLS PROMOTES COLONIC INFLAMMATION AND COLITIS-ASSOCIATED CANCER