Colorectal cancer (CRC) is a public health threat in the United States. Because the colon contains the most densely populated microbial ecosystem known, there has been a longstanding interest in how environmental exposure of colonic epithelial cells to the microbiota contributes to the initiation and/or progression of human CRC. Our data accrued in CRC and healthy colonoscopy control populations reveal that combined approaches, structural microbiology and genomics, yield novel observations regarding the impact of the microbiota on the host colon mucosa. Namely, right (proximal) colon cancers (before the hepatic flexure) and their paired normal mucosal samples far distant from the CRCs are nearly universally covered by complex bacterial biofilms that exhibit bacterial invasion into all tumors and some normal colon tissues whereas left (distal) CRCs and normal tissues infrequently exhibit biofilms. In the healthy colonoscopy (non-tumor) host, only ~10-15% of colon tissues exhibit mucosal biofilms without geographic preference indicating the right colon is not natively associated with biofilm formation. Importantly, biofilm formation correlates with procarcinogenic pathway activation and crypt cell proliferation in tumor and non-tumor host colon tissues. Thus, we hypothesize that the proximal colon is susceptible to marked changes in bacterial organization that drive carcinogenesis. We will test our hypothesis using experimental approaches applied to a clinical colonoscopy cohort.
Our specific aims are: 1) to establish the natural history of colon mucosal biofilm development; and 2) to define bacterial community and host mechanisms by which biofilms contribute to colon carcinogenesis. Our results will provide guidance to development of new tools for the prevention of CRC.

Public Health Relevance

Colorectal cancer is a leading preventable cause of illness and death in the United States. Increasing information supports that bacteria in the colon contribute to causing colon cancer. This proposal will further define how colon bacteria contribute to colon cancer and the mechanisms by which organized bacterial structures called biofilms induce cancer-promoting changes in the colon mucosa.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-PSE-K (90)S)
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Daschner, Phillip J
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Hurtado, Christopher G; Wan, Fengyi; Housseau, Franck et al. (2018) Roles for Interleukin 17 and Adaptive Immunity in Pathogenesis of Colorectal Cancer. Gastroenterology 155:1706-1715
Chen, Jie; Domingue, Jada C; Sears, Cynthia L (2017) Microbiota dysbiosis in select human cancers: Evidence of association and causality. Semin Immunol 32:25-34
Drewes, Julia L; White, James R; Dejea, Christine M et al. (2017) High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia. NPJ Biofilms Microbiomes 3:34