My laboratory focuses on the pathogenesis of colon disease by enteric bacteria using enterotoxigenic Bacteroides fragilis (ETBF) as a model for inducing colon inflammation. We identified the B. fragilis toxin gene (bft), purified the protein (BFT) and defined its mechanism of action in vitro. More recently, we established in vivo models of ETBF colitis and colon tumorigenesis. Using these models, we have identified that ETBF induce selective Stat3/Th17 immune responses in the colon and that these pathways, at least in part, contribute to colon tumorigenesis. Our data were the first to report this mechanism for inflammation-induced endogenous colon tumor induction in response to colon colonization with a human commensal (up to 40% of ETBF-colonized humans are asymptomatic). We are extending this work to human studies to understand the microbial contribution to colitis and colon cancer pathogenesis. Our studies include the molecular mechanisms by which BFT and ETBF induce colon carcinogenesis including identifying the BFT receptor, defining BFT-induced activation of colonic epithelial signaling pathways, determining the immunologic determinants of colon carcinogenesis and establishing the genetic and epigenetic mutations contributing to colon tumor induction and promotion stimulated by ETBF through BFT.
Most relevant to the current application
- Chambers FG, Koshy SS, Saidi R, Clark DP, Sears CL. . Bacteroides fragilis toxin exhibits polar activity on monolayers of human intestinal epithelial cells (T84 cells) in vitro. Infec. Immun. . 1997;(65):3561- 3570. PMCID: Prior to April 2008.
- Wu S, Lim K-C, Huang J, Saidi SF, Sears CL. . The Bacteroides fragilis toxin cleaves the Zonula Adherens Protein, E-cadherin. Proc. Natl. Acad. Sci. USA. . 1998;(95):14979- 14984. PMCID: Prior to April 2008.
- Riegler M, Lotz M, Sears CL, Pothoulakis C, Castagliuolo I, Wang CC, Sedivy R, Sogukoglu T, Cosentini E, Bischof G, Feil W, Teleky B, Hamilton G, LaMont JT and Wenzl E. . Bacteroides fragilis toxin 2 damages human colonic mucosa in vitro. Gut . 1999;(44):504-510. PMCID: Prior to April 2008.
- Wu S, Morin PJ, Maouyo D, Sears CL. . Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation Gastroenterology. 2003;(124):392-400. PMCID: Prior to April 2008.
- Wu S, Powell J, Mathioudakis N, Kane S, Fernandez E, Sears CL. Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 (IL-8) through mitogen activated protein kinases and a tyrosine kinase-regulated Nuclear Factor-?? pathway Infec Immun . 2004;(72):5832-5839. PMCID: Prior to April 2008.
- Wu S, Shin JW, Cohen M, Zhang G, Sears CL. . The Bacteroides fragilis toxin binds to a specific intestinal epithelial cell receptor. Infection & Immunity Infection & Immunity . 2006;(74):5832-5390. PMCID: Prior to April 2008.
- Wu S, Zhang M, Franco AA, Rhee K, Sears CL. Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and activates E-cadherin cleavage dependent on cellular γsecretase. J Cell Science . 2007;(120):1944-1952. PMCID: Prior to April 2008.
- Sears CL, Islam S, Saha A, Arjumand M, Alam NH, Faruque ASG, Salam MA, Shin J, Hecht D, Weintraub A, Sack RB, Qadri F. Association of Enterotoxigenic Bacteroides fragilis infection with inflammatory diarrhea. Clinical Infect Dis . 2008;(47):797-803. PMCID: 3045827.
- Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM, Sears CL. A human colonic commensal promotes colon tumorigenesis via activation of Thelper type 17 T cell responses. Nature Medicine. 2009;(15):1016-1022. PMCID: 3034219.
- Sears CL. Enterotoxigenic Bacteroides fragilis: A Rogue among Symbiotes. Clinical Microbiology Reviews. 2009;(22):349-369. PMCID: 2963065.
- Rhee KJ, Wu S, Wu X, Huso DL, Karim B, Franco AA, Rabizadeh S, Golub J, Mathews LE, Shin J, Sartor RB, Golenbock D, Hamad, A, Gan CM, Housseau F, Sears CL. Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57Bl/6 mice. Infec Immun . 2009;(77):1708-1718. PMCID: 2663167.
- Goodwin AC, Destefano Shields CE, Wu S, Huso DL, Wu X, Murray-Stewart TR, Hacker-Prietz A, Rabizadeh S, Woster PM, Sears CL, Casero RA. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc Natl Acad Science 108:15354-9, 2011/
- Wick EC, Leblanc RE, Ortega G, Robinson C, Platz E, Pardoll DM, Iacobuzio-Donahue C, Sears CL. Shift from pStat6 to pStat3 predominance is associated with inflammatory bowel disease-associated dysplasia. Inflamm Bowel Dis 18:1267-74, 2012. PMCID:3266961
- O’Hagan HM, Wang W, Sen S, Destefano Shields C, Lee SS, Zhang YW, Clements EG, Cai Y, Van Neste L, Easwaran H, Casero RA, Sears CL, Baylin SB. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and Polycomb members to promoter CpG islands. Cancer Cell 15:606-619, 2011. PMCID:3220885
- Dejea C, Wick E, Sears CL. Bacterial oncogenesis in the colon. Future Microbiology 8(4):445-460, 2013. PMCID (in progress).
Ongoing Research Support
09/02/10 - 07/31/15
NIH/NCI Enterotoxigenic Bacteroides fragilis: A bacterial promoter of colon oncogenesis. This project will test whether detection of ETBF and/or the colon immune response to ETBF in humans provide new, easier approaches to the prevention of the morbidity and mortality due to colon cancer.(PI)
07/06/10 - 04/30/15
NIH/NCI Mechanisms of TH17 Inflammation-Induced Colon Carcinogenesis. This project will study the immune and genetic mechanisms by which a newly recognized common human stool bacterium called enterotoxigenic Bacteroides fragilis (ETBF) triggers colon tumors in mice, providing new insights into how colon cancer develops and potentially new approaches to colon cancer therapy. (PI)
04/22/13 - 04/22/15
Merieux Institute Induction of Human Colon Cancer by BFT producing Bacteroides Species. Induction of Human Colon Cancer by BFT producing Bacteroides Species The goal of this project is to validate the association of bft-expressing Bacteroides species with CRC and further, to identify targets for development of sensitive and specific diagnostics to identify patients at potential high risk for CRC. (PI)
07/01/12 - 06/30/14
NIH/NCI Microbial Induction of Colon Cancer and Mechanisms. This project will integrate microbiota, immunologic and metabolomic data to identify novel biomarkers with potential to enhance the prevention and detection of human colon cancer.(PI)
07/01/12 - 06/30/14
SWAMI Johns Hopkins Swami Institute for Intl. Medical Edu. The goal of this project is to prospectively study the role of the microbiome and enterotoxigenic Bacteroides fragilis (ETBF) in CRC in Kuala Lumpur, Malaysia.(Co-Investigator)
R01CA179440 Sears 07/01/13-06/30/18
GPR35: Role in Colonic Inflammation and Oncogenesis
This project test the hypothesis that GPR35, known to be highly expressed in the colon and previously linked to gastric cancer induction, is the CEC receptor hijacked by BFT and a critical contributor to colon carcinogenesis, thereby, providing a direct molecular link between a common microbiota member and CRC pathogenesis.
Completed Research Support
05/01/08 - 02/28/13
NIH/NIDDK Mechanisms of Interleukin-17 Inflammation Induced by Bacteroides Fragilis
08/20/93 - 06/30/12
NIH/NIDDK Physiology and Cloning of B Fragilis Enterotoxin
07/13/01 - 08/31/11
NIH/NCI Howard/Hopkins Cancer Center Partnership - Project 1- Gut Flora and Colon Cancer in African Americans (Co-Investigator)
08/01/06 - 07/31/11
NIH/NIAID Research Training in Microbial Diseases(Co-Investigator)
08/01/11 - 07/31/13
L2 Diagnostics (sub contract)Induction Of Human Colon Cancer by BFT producing Bac SpeciesThe goal of this project is development of a real-time polymerase chain for quantification of enterotoxigenic Bacteroides fragilis (ETBF) in human stool samples.(PI)
01/01/09 - 12/31/13
NIH/NCI Polyamine Oxidases as Antitumor TargetsThe goal of this project is to understand how polyamine oxidases contribute to oncogenesis. ETBF-infected mice are used as one model in this grant.(Co-Investigator)