My laboratory focuses on studies to determine how the microbiota contributes to colorectal cancer. We have studied in detail the carcinogenic bacterium, enterotoxigenic Bacteroides fragilis (ETBF), using this organism as a model for inducing colon inflammation and carcinogenesis. Over time, we identified the B. fragilis toxin gene (bft), purified the protein (BFT) and defined its mechanism of action in vitro. Subsequently, we established in vivo models of ETBF colitis and colon tumorigenesis. Using these models, we 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 a Th17 mechanism for inflammation-induced endogenous colon tumor induction; subsequent work by other groups has confirmed the importance of Th17/IL-17 mechanisms in many cancers including human colon cancer. We subsequently turned our attention to identifying bacterial contributions to human colon cancer. This work led us to propose the hypothesis that biofilm-associated colon mucosal pro-carcinogenesis marks an early event in the biology of colonic epithelial cell transformation in a subset of sporadic colon cancers. This hypothesis is now being tested in a prospective NCI-supported study involving 2000 individuals undergoing screening colonoscopy with mechanistic work conducted in germ-free mice. We have extended our work to Familial Adenomatous Polyposis (FAP) to further test the hypothesis that the microbiota and potentially specific bacterial species contribute to colon carcinogenesis. This work represents the earliest stage of colon polyposis at which microbiota disease associations and mechanisms have been examined to date. Our long-term goal is to devise ways to utilize the microbiota markers to identify and better predict those at risk for colon carcinogenesis.
Drewes JL, White JR, Dejea CM, Fathi P, Iyadorai T, Vadivelu J, Roslani AC, Wick EC, Mongodin EF, Loke MF, Thulasi K, Gan HM, Goh KL, Chong HY, Kumar T, Wanyiri JW, and Sears CL. High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia. NPJ Biofilms Microbiomes. 2017; 3:34.
Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB, Tam AJ, McAllister FM, Fan H, Wu X, Ganguly S, Lebid A, Metz P, Van Meerbeke SW, Huso DL, Wick EC, Pardoll DM, Wan F, Wu S, Sears CL*, and Housseau F*. Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells. Cell Host Microbe. 2018 March 14; 23(3): 421. *co-senior authors.
Dejea CM, Fathi P, Craig JM, Boleij A, Taddese R, Geis AL, Wu1 X, DeStefano Shields CE, Hechenbleikner EM, Huso DL, Anders RA, Giardiello FM, Wick EC, Wang H, Wu S, Pardoll DM, Housseau F, and Sears CL. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science. 2018 Feb 02; 359: 6375: 592-597.
Dejea CM, Wick EC, Hechenbleikner EM, White JR, Mark Welch JL, Rossetti BJ, Peterson SN, Snesrud EC, Borisy GG, Lazarev M, Stein E, Vadivelu J, Roslani AC, Malik AA, Wanyiri JW, Goh KL, Thevambiga I, Fu K, Wan F, Llosa N, Housseau F, Romans K, Wu X, McAllister FM, Wu S, Vogelstein B, Kinzler KW, Pardoll DM, Sears CL. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci U S A. 2014 PMID: 25489084.
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 T helper type 17 T cell responses. Nat Med. 2009 PMID: 19701202.