Colorectal cancer (CRC), the second leading cause of cancer death in the U.S., has long been recognized as a genetic disease. Advancement in microbial detection technology has revolutionized our view of many human diseases, and infectious etiologies have been suggested for CRC. Fusobacterium nucleatum (Fn), a gram-negative common oral anaerobe, has been shown to stimulate CRC via its unique FadA adhesin. The goal of the current proposal is to investigate the mechanisms by which Fn promotes CRC. FadA stimulates CRC cell growth by binding to E-cadherin and activating -catenin signaling. Such stimulation is specific for colorectal carcinoma cells because FadA binding to other types of cells does not stimulate cell growth. We hypothesize that Fn stimulates CRC in conjunction with specific host genetic mutations. Since CRC initiates from cancer stem cells in the colon, we further hypothesize that Fn interacts with specific cancer-initiating stem cells to promote CRC. To test these hypotheses, we propose two specific aims: (i) To determine the host and bacterial components specific for Fn-stimulated colorectal tumorigenesis in vitro; and (ii) to investigate how Fn stimulates colorectal tumorigenesis in vivo. From this study, we anticipate gaining novel insights into the mechanism of colorectal tumorigenesis, and identify novel therapeutic targets for prevention and treatment of CRC. Thus, it implies significant translational potential.

Public Health Relevance

Colorectal cancer (CRC) is the second leading cause of cancer death in the U.S. Fusobacterium nucleatum (Fn), a common oral bacterium, has recently been indicated to stimulate CRC. This study investigates how F. nucleatum drives CRC. The results will advance our understanding of colorectal carcinogenesis and identify novel diagnostic and therapeutic targets for CRC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA192111-04
Application #
9378094
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Han, Yiping W (2015) Fusobacterium nucleatum: a commensal-turned pathogen. Curr Opin Microbiol 23:141-7
Nie, Shuping; Tian, Baoyu; Wang, Xiaowei et al. (2015) Fusobacterium nucleatum subspecies identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry. J Clin Microbiol 53:1399-402