Role of Stat3 in ETBF Mediated Colitis and Tumor Initiation

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Sporadic colorectal cancer (CRC), the second leading cause of death in the United States, is a major public health problem for which there are no clear preventive measures. The basis for my work is the discovery that Min (APC+/-) mice colonized with a human colonic commensal, enterotoxigenic Bacteriodes fragilis (ETBF), develop colonic inflammation and rapid colon tumor formation that are partly dependent on a predominant and selective Th17 response. Newly acquired preliminary data demonstrate that ETBF-colonized lethally irradiated Min mice with transplanted marrow from IL17R-/- mice (IL17R KO exclusively on epithelial cells) fail to develop tumors at 3 months. This proposal focuses on defining the contribution of commensal flora in ETBF-induced IL- 17 colitis and tumorigenesis. It is intended to complement my ongoing K08 experiments, which center on evaluating Stat3, a key Th17 pathway transcription factor, in ETBF-induced tumorigenesis. The goal of this proposal is to begin to investigate how ETBF and/or commensal organisms contribute to the mucosal IL-17 response in ETBF colitis. In vitro, the ETBF toxin, BFT, binds to a specific epithelial cell receptor, stimulates cleavage of the intracellular adhesion protein E-cadherin and triggers rapid activation of signal transduction pathways and increased cellular permeability. In vivo, ETBF increases barrier permeability, permitting the commensal bacteria to directly interact with the mucosal immune cells. Prevailing evidence suggests that, under certain contexts, after a breach in the epithelial cell barrier, commensal bacteria can promote oncogenic innate and adaptive immune responses via toll like receptor (TLR) signaling. The ETBF Min model of CRC provides a unique approach for understanding how a specific human bacterium (ETBF) alone or in concert with other commensal organisms, is able to induce tumorigenesis. Understanding the overall role of the microbiome in initiation and promotion of CRC is highly innovative. The results of the experiments in this proposal will serve as preliminary data for an R01 submission focused on mechanisms of IL-17 initiation in ETBF-mediated tumorigenesis. My long-term goal is to understand the mechanism of initiation of the oncogenic IL-17 response associated with human CRC. Recent studies demonstrate, in early stage human CRC, a Th17 signature is associated with worse prognosis. Therefore, mechanistic understanding may ultimately allow for development of immune modulating prevention and treatment strategies for human CRC.