Colorectal cancer (CRC) is the second leading cause of cancer-related death and the third most common cancer in the US. Inflammation is a key contributor to carcinogenesis, and there is an increased incidence of cancer in patients with chronic inflammatory diseases. Inflammation in the tumor microenvironment can enhance cancer cell proliferation, survival, and migration. A chronically inflamed colonic mucosa is pro- neoplastic;and ulcerative colitis (UC) is one of the highest risk factors for the development of CRC. Recent data suggest that immune responses to commensal gut bacteria may influence the development of CRC and colitis-associated colorectal cancer (caCRC). However, how the gut microbiota shapes mucosal immune responses leading to chronic inflammation and CRC is not well understood. Important questions include: (1) what are the features of the gut microbiota that elicit chronic inflammatory responses that drive caCRC and (2) how do mucosal innate immune subsets function in the evolving tumor microenvironment. This proposal builds on our recent studies of a spontaneous mouse model of UC and caCRC that is driven genetically by T-bet deficiency in the absence of adaptive immunity, and stems from our preliminary data on the microbial communities that instigate colitis.
Our specific aims are to: 1) define the role of fecal microbial community members in initiating the innate immune driven inflammatory cascades that drive caCRC;2) characterize monocyte populations and their recruitment, function, and response to the intestinal microbiota across the colitis r dysplasia r adenocarcinoma transition;and 3) perform a functional genomic analysis of fecal microbial communities across the colitis r dysplasia r adenocarcinoma transition. We employ cell biology, immunology, and microbiology techniques and sequencing technology as experimental tools, in conjunction, with computational methodology capable of integrating these diverse data sets. By analyzing the function of intestinal microbial communities and innate immune subsets in driving pro-neoplastic inflammation, this proposal will advance basic understanding of the contribution of host-microbial interactions to the evolution of a tumor microenvironment. Since we utilize a mouse model that is reminiscent of UC and recapitulates key features of human IBD-associated CRC, we anticipate that our data will be applicable for human disease and for the development of anti-inflammatory host and/or microbe directed therapeutics that will prevent the development and progression of cancer.

Public Health Relevance

Colorectal cancer is the second leading cause of cancer-related death and the third most common cancer in the US;and inflammation is a key contributor to carcinogenesis. Our proposal examines the role of inflammatory cells and gut bacteria in driving cancer in the colon.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA154426-04
Application #
8607163
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
2011-03-18
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$301,602
Indirect Cost
$114,852
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Rooks, Michelle G; Veiga, Patrick; Wardwell-Scott, Leslie H et al. (2014) Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission. ISME J 8:1403-17
Sears, Cynthia L; Garrett, Wendy S (2014) Microbes, microbiota, and colon cancer. Cell Host Microbe 15:317-28
Kostic, Aleksandar D; Howitt, Michael R; Garrett, Wendy S (2013) Exploring host-microbiota interactions in animal models and humans. Genes Dev 27:701-18
Smith, Patrick M; Howitt, Michael R; Panikov, Nicolai et al. (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569-73
Kostic, Aleksandar D; Chun, Eunyoung; Robertson, Lauren et al. (2013) Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14:207-15
Segata, Nicola; Boernigen, Daniela; Tickle, Timothy L et al. (2013) Computational meta'omics for microbial community studies. Mol Syst Biol 9:666
Kostic, Aleksandar D; Gevers, Dirk; Pedamallu, Chandra Sekhar et al. (2012) Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 22:292-8