Specific configurations of the gut microbiome have been associated with colorectal cancer (CRC), but how gut microbes, their metabolites, and their interactions with the immune system potentiate colorectal carcinogenesis remains poorly understood. Fusobacterium nucleatum, a Gram-negative anaerobic bacterium, is a normal constituent of the human oral microbiome; however, numerous studies now demonstrate that F. nucleatum (Fn) is enriched in human colorectal adenomas and CRC compared to healthy colonic tissues. While our group has been involved in several of these studies under the aegis of this award; exactly how Fn promotes colonic tumorigenesis has not been fully elucidated. Clarifying the mechanisms by which Fn shapes the colonic tumor microenvironment will provide important insight for embarking on a multipronged approach to use Fn as a diagnostic and therapeutic target in CRC prevention and treatment. Based on the findings from our first funding cycle for this competitive R01 renewal, we formulate the overarching hypothesis that Fn is an oncomicrobe that through its effects on the CRC tumoral microbiota, via its oncometabolites, and by its direct interactions with intratumoral immune cells contributes to CRC growth and progression. Leveraging our knowledge and expertise with Fn, meta'omics, and mouse models, we will address how Fn potentiates colorectal carcinogenesis in its role as an oncomicrobe, via its short-chain fatty acids (oncometabolites), and in its interactions within the tumor immune microenvironment (oncoimmunology).

Public Health Relevance

Colorectal cancer (CRC) is a global health problem. CRC is the third highest cause of cancer-related death worldwide and leading cause of cancer-related death in non-smokers. Herein we study the contribution of Fusobacterium nucleatum to the development of colorectal cancer using preclinical models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA154426-09
Application #
9977924
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
2011-03-18
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
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