Patients with long-standing ulcerative colitis (UC) are at increased risk for the development of colon cancer. The morbidity associated with long-standing disease could be minimized with biological markers allowing for risk stratification of an individual's dysplastic lesion and identification of chemopreventative approaches which might prevent or reverse dysplasia in this high-risk population. A major limitation in identifying important markers and therapeutic agents for IBD-associated neoplasia, however, is that most mechanisms are studied in cell culture systems involving sporadic colon cancers or in animal models of colitis-associated cancer that do not closely phenocopy IBD-associated cancer. To overcome these limitations, the objective of this proposal is to develop and test the functional properties of an organoid-based culture system from ulcerative colitis tissues and ulcerative colitis-associated dysplasia. This methodology and tissue bank will lay the groundwork for future studies focused on studying mechanisms, identifying markers, and investigating therapies for colorectal neoplasia in IBD. In previous studies, we demonstrated the tumor-suppressor, miR-193a-3p is lost in UC-associated cancer and that this miRNA regulates cellular proliferation and oncogenic signals. As such, we will test the hypothesis that restoration of miR-193a-3p suppresses inflammation-driven cell autonomous growth and inhibits neoplastic features of dysplastic lesions from patients with ulcerative colitis using organoid tissues. We will use investigations into this miRNA as a proof of concept that colonoids from IBD-associated neoplastic tissues retain biologic properties from original tissue and can be used to study functional properties of carcinogenesis. To test this hypothesis, we propose two aims. 1) Characterize miRNA expression patterns from colonoids created from UC and UC-associated neoplasia. 2) Dissect the causal relationship between miR-193a-3p loss, inflammation, and malignant transformation in ulcerative colitis. The methodology proposed in these studies is expected to overcome inherent difficulties encountered in previous in vitro and animal studies focusing on IBD- associated neoplasia and is likely to lead to increased clinical relevance of work understanding mechanisms and testing treatment strategies, thereby establishing a personalized approach to clinical management for this high-risk population.
The proposed research is relevant to public health because the prevalence of inflammatory bowel disease is increasing and patients with long-standing disease are at a high risk for developing colorectal cancer. Therefore, developing models to better understand mechanisms and treatments for dysplastic lesions in inflammatory bowel disease ultimately may lead to a personalized approach for each patient minimizing the morbidity and cost associated with the disease.
|Pekow, Joel; Meckel, Katherine; Dougherty, Urszula et al. (2017) miR-193a-3p is a Key Tumor Suppressor in Ulcerative Colitis-Associated Colon Cancer and Promotes Carcinogenesis through Upregulation of IL17RD. Clin Cancer Res 23:5281-5291|