MUC1-C IS A DRUGGABLE TARGET FOR TREATMENT OF COLITIS AND PROGRESSION OF COLITIS-ASSOCIATED COLORECTAL CANCER

The MUC1-C oncoprotein evolved in mammals to protect epithelial cells, such as those lining the gastrointestinal tract, from loss of homeostasis. In this way, MUC1-C activates pathways that contribute to inflammation, proliferation and remodeling associated with the wound healing response. MUC1-C is upregulated in human tissues from inflamed ulcerative colitis (UC) mucosa as compared to that from normal and uninflamed UC mucosa. MUC1-C is also upregulated in a mouse MUC1+/-/IL-10-/- model of colitis, consistent with its involvement in the inflammatory response. MUC1-C forms a direct complex with NF-κB p65 and promotes the activation of NF-κB target genes, including MUC1 itself in an auto- inductive circuit. MUC1-C thereby drives proinflammatory NF-κB pathway genes in human inflamed UC tissues and in the genetically engineered mouse model (GEMM) of colitis. Mechanistically, MUC1-C induces the TGF-b-activated kinase 1 (TAK1), which is an essential effector of proinflammatory NF-κB signaling. Of further significance, MUC1-C drives the TAK1→NF-κB p65 pathway in human colon cancer cell lines, and MUC1 and TAK1 are upregulated in human colon cancers. These seminal findings supported the notion that MUC1-C contributes to colitis and progression to colon cancer. To extend these studies, MUC1-C was targeted with an inhibitor that blocks its homodimerization and function. Remarkably, treatment of the MUC1+/-/IL-10-/- GEMM with the GO-203 inhibitor was associated with decreases in the severity of colitis and progression of colitis to dysplasia and carcinomas. Intestinal stem cells (ISCs) that express Lgr5 are of importance in the inflammatory response to colitis and in progression to colitis-associated colorectal cancer (CACC). Targeting MUC1-C with GO-203 in mouse models of colitis suppressed Lgr5 expression, as well as induction of MYC and other core pluripotency factors. By extension to human colon cancer cells, we found that MUC1- C drives MYC with activation of LGR5 and stemness. MUC1-C also induces cancer stem cell (CSC) markers (BMI1, ALDH1, FOXA1, LIN28B) and the OCT4, SOX2, and NANOG pluripotency factors. Consistent with driving the CSC state, targeting MUC1-C suppressed the capacity of CRC cells to promote wound healing, invasion, self-renewal, and tumorigenicity. Analysis of human tissues further demonstrated that MUC1 expression associates with activation of inflammatory pathways, development of colitis, and aggressiveness of CRCs. These results collectively indicate that MUC1-C is of importance for integrating stemness and pluripotency in colitis and CRC. Of clinical relevance, the findings further indicate that MUC1-C represents a previously unrecognized target that is potentially druggable with orally administered GO-203 now being tested in the GEMMs for treating progression of colitis and CRC.