Christopher Shawn Williams, M.D., Ph.D.
Associate Professor of Medicine (Gastroenterology, Hepatology & Nutrition)
Associate Professor of Cancer Biology
Vanderbilt University Medical Center, Gastroenterology Division
1030-C Medical Research Building IV
Nashville, TN 37232-0252
1) Epigenetic control of intestinal epithelial wound healing and repair programs and relationship to colorectal oncogenesis. 2) Junctional signaling in mucosal wound healing responses and inflammatory carcinogenesis. 3) Oxidative injury defenses in Inflammatory Bowel Disease (IBD) and colitis associated carcinoma (CAC).
Our research program focuses on understanding how the epithelium responds to injury and how normal injury response processes are subverted in the development of malignancy. The research activities span the basic to translational spectrum. We have three major research programs within the lab:
1) Epigenetic control of intestinal epithelial wound healing and repair programs and relationship to colorectal oncogenesis.
We are studying the role of the Myeloid Translocation Gene (MTGs) family in intestinal biology with emphasis on gut development, stem cell function, wound healing and malignancy. MTGR1 (Myeloid Translocation Gene, Related-1), MTG8 and MTG16 are members of a gene family originally identified as targets of chromosomal translocation in acute myeloid leukemia (AML). MTG family members act as transcriptional repressors and interact with other corepressors mSin3, N-CoR/SMRT and histone deacetylases (HDAC1-3). Chromosomal translocations often target master regulatory genes that affect growth, differentiation and apoptosis.
Using unique mouse models we are characterizing MTGs as modifiers of WNT dependent tumorigenesis in the gut and deterring how the regulate stem cell programs.
2) Junctional signaling in mucosal wound healing responses and inflammatory carcinogenesis.
We recently determined that a tight junction associated protein called BVES was suppressed by promoter methylation in colon cancer and that it regulates epithelial to mesenchymal transition (EMT) influencing metastasis.
We are currently cataloging the BVES protein interactome as a means to understand how BVES transduces "Out to In" signaling. In addition, using Bves-null mice, we are dissecting its role in intestinal wound healing using chemical, infectious, and mechanical colonic injury modeling and its role in colitis associated cancer.
3) Oxidative injury defenses in Inflammatory Bowel Disease (IBD) and colitis associated carcinoma (CAC).
Little is known about the role of selenium and selenoproteins in inflammatory bowel disease (IBD), a condition of intermittent severe oxidative stress. We have shown that selenium deficiency results in increased mucosal injury and progression to colitis-associated dysplasia (CAD). Likewise, germ line Sepp1 and Gpx3 mutant mice had increased tumor burden with major effects on proliferation, apoptosis and DNA damage.
We hypothesize that intestinal Sepp1 alters the inflammatory microenvironment via clearance of reactive oxygen species thus affecting epithelial stem cell and differentiation programs. We are determining which stem cell pathways are modified by selenoproteins in influencing tumorigenesis.
- Singh, K, Coburn, LA, Barry, DP, Asim, M, Scull, BP, Allaman, MM, Lewis, ND, Washington, MK, Rosen, MJ, Williams, CS, Chaturvedi, R, Wilson, KT Deletion of cationic amino acid transporter 2 exacerbates dextran sulfate sodium colitis and leads to an IL-17-predominant T cell response. Am J Physiol Gastrointest Liver Physiol, 305(3), G225-40, 2013.
- Barrett, CW, Singh, K, Motley, AK, Lintel, MK, Matafonova, E, Bradley, AM, Ning, W, Poindexter, SV, Parang, B, Reddy, VK, Chaturvedi, R, Fingleton, BM, Washington, MK, Wilson, KT, Davies, SS, Hill, KE, Burk, RF, Williams, CS Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis. PLoS One, 8(7), e67845, 2013.
- Coburn, LA, Horst, SN, Chaturvedi, R, Brown, CT, Allaman, MM, Scull, BP, Singh, K, Piazuelo, MB, Chitnavis, MV, Hodges, ME, Rosen, MJ, Williams, CS, Slaughter, JC, Beaulieu, DB, Schwartz, DA, Wilson, KT High-throughput multi-analyte Luminex profiling implicates eotaxin-1 in ulcerative colitis. PLoS One, 8(12), e82300, 2013.
- Rosen, MJ, Chaturvedi, R, Washington, MK, Kuhnhein, LA, Moore, PD, Coggeshall, SS, McDonough, EM, Weitkamp, JH, Singh, AB, Coburn, LA, Williams, CS, Yan, F, Van Kaer, L, Peebles, RS, Wilson, KT STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines. J Immunol, 190(4), 1849-58, 2013.
- Barrett, CW, Ning, W, Chen, X, Smith, JJ, Washington, MK, Hill, KE, Coburn, LA, Peek, RM, Chaturvedi, R, Wilson, KT, Burk, RF, Williams, CS Tumor suppressor function of the plasma glutathione peroxidase gpx3 in colitis-associated carcinoma. Cancer Res, 73(3), 1245-55, 2013.
- Barrett, CW, Smith, JJ, Lu, LC, Markham, N, Stengel, KR, Short, SP, Zhang, B, Hunt, AA, Fingleton, BM, Carnahan, RH, Engel, ME, Chen, X, Beauchamp, RD, Wilson, KT, Hiebert, SW, Reynolds, AB, Williams, CS Kaiso directs the transcriptional corepressor MTG16 to the Kaiso binding site in target promoters. PLoS One, 7(12), e51205, 2012.
- Coburn, LA, Gong, X, Singh, K, Asim, M, Scull, BP, Allaman, MM, Williams, CS, Rosen, MJ, Washington, MK, Barry, DP, Piazuelo, MB, Casero, RA, Chaturvedi, R, Zhao, Z, Wilson, KT L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis. PLoS One, 7(3), e33546, 2012.
- Williams, CS, Bradley, AM, Chaturvedi, R, Singh, K, Piazuelo, MB, Chen, X, McDonough, EM, Schwartz, DA, Brown, CT, Allaman, MM, Coburn, LA, Horst, SN, Beaulieu, DB, Choksi, YA, Washington, MK, Williams, AD, Fisher, MA, Zinkel, SS, Peek, RM, Wilson, KT, Hiebert, SW MTG16 contributes to colonic epithelial integrity in experimental colitis. Gut, 2012.
- Williams, CS, Zhang, B, Smith, JJ, Jayagopal, A, Barrett, CW, Pino, C, Russ, P, Presley, SH, Peng, D, Rosenblatt, DO, Haselton, FR, Yang, JL, Washington, MK, Chen, X, Eschrich, S, Yeatman, TJ, El-Rifai, W, Beauchamp, RD, Chang, MS BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma. J Clin Invest, 121(10), 4056-69, 2011.
- Russ, PK, Pino, CJ, Williams, CS, Bader, DM, Haselton, FR, Chang, MS Bves modulates tight junction associated signaling. PLoS One, 6(1), e14563, 2011.
- Barrett, CW, Fingleton, B, Williams, A, Ning, W, Fischer, MA, Washington, MK, Chaturvedi, R, Wilson, KT, Hiebert, SW, Williams, CS MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model. Cancer Res, 71(4), 1302-12, 2011.
- Hong, SK, Chaturvedi, R, Piazuelo, MB, Coburn, LA, Williams, CS, Delgado, AG, Casero, RA, Schwartz, DA, Wilson, KT Increased expression and cellular localization of spermine oxidase in ulcerative colitis and relationship to disease activity. Inflamm Bowel Dis, 16(9), 1557-66, 2010.
- Whittem, CG, Williams, AD, Williams, CS Murine Colitis modeling using Dextran Sulfate Sodium (DSS). J Vis Exp, (35), 2010.
- Farmer, TE, Williams, CS, Washington, MK, Hiebert, SW Inactivation of the p19(ARF) tumor suppressor affects intestinal epithelial cell proliferation and integrity. J Cell Biochem, 104(6), 2228-40, 2008.
- Moore, AC, Amann, JM, Williams, CS, Tahinci, E, Farmer, TE, Martinez, JA, Yang, G, Luce, KS, Lee, E, Hiebert, SW Myeloid Translocation Gene Family Members Associate with TCFs and Influence TCF-Dependent Transcription. Mol Cell Biol, 2007.
- Martinez, JA, Williams, CS, Amann, JM, Ellis, TC, Moreno-Miralles, I, Washington, MK, Gregoli, P, Hiebert, SW Deletion of Mtgr1 sensitizes the colonic epithelium to dextran sodium sulfate-induced colitis. Gastroenterology, 131(2), 579-88, 2006.
- Smith, DS, Williams, CS, Ferris, CD Diagnosis and treatment of chronic gastroparesis and chronic intestinal pseudo-obstruction. Gastroenterol Clin North Am, 32(2), 619-58, 2003.
- Aklog, L, Williams, CS, Byrne, JG, Goldhaber, SZ Acute pulmonary embolectomy: a contemporary approach. Circulation, 105(12), 1416-9, 2002.
- Williams, CS, Sheng, H, Brockman, JA, Armandla, R, Shao, J, Washington, MK, Elkahloun, AG, DuBois, RN A cyclooxygenase-2 inhibitor (SC-58125) blocks growth of established human colon cancer xenografts. Neoplasia, 3(5), 428-36, 2001.
- Mann, M, Sheng, H, Shao, J, Williams, CS, Pisacane, PI, Sliwkowski, MX, DuBois, RN Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterology, 120(7), 1713-9, 2001.
- Williams, CS, Watson, AJ, Sheng, H, Helou, R, Shao, J, DuBois, RN Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res, 60(21), 6045-51, 2000.
- Williams, CS, Tsujii, M, Reese, J, Dey, SK, DuBois, RN Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest, 105(11), 1589-94, 2000.
- Callejas, NA, BoscÃ¡, L, Williams, CS, DuBOIS, RN, MartÃn-Sanz, P Regulation of cyclooxygenase 2 expression in hepatocytes by CCAAT/enhancer-binding proteins. Gastroenterology, 119(2), 493-501, 2000.
- Sheng, H, Shao, J, Dixon, DA, Williams, CS, Prescott, SM, DuBois, RN, Beauchamp, RD Transforming growth factor-beta1 enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J Biol Chem, 275(9), 6628-35, 2000.
- Williams, CS, Goldman, AP, Sheng, H, Morrow, JD, DuBois, RN Sulindac sulfide, but not sulindac sulfone, inhibits colorectal cancer growth. Neoplasia, 1(2), 170-6, 1999.
- Williams, CS, Shattuck-Brandt, RL, DuBois, RN The role of COX-2 in intestinal cancer. Expert Opin Investig Drugs, 8(1), 1-12, 1999.
- Williams, CS, Mann, M, DuBois, RN The role of cyclooxygenases in inflammation, cancer, and development. Oncogene, 18(55), 7908-16, 1999.
- Sheng, H, Williams, CS, Shao, J, Liang, P, DuBois, RN, Beauchamp, RD Induction of cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway. J Biol Chem, 273(34), 22120-7, 1998.
- Goldman, AP, Williams, CS, Sheng, H, Lamps, LW, Williams, VP, Pairet, M, Morrow, JD, DuBois, RN Meloxicam inhibits the growth of colorectal cancer cells. Carcinogenesis, 19(12), 2195-9, 1998.
- Sheng, H, Shao, J, Williams, CS, Pereira, MA, Taketo, MM, Oshima, M, Reynolds, AB, Washington, MK, DuBois, RN, Beauchamp, RD Nuclear translocation of beta-catenin in hereditary and carcinogen-induced intestinal adenomas. Carcinogenesis, 19(4), 543-9, 1998.
- Inoue, I, Nakajima, T, Williams, CS, Quackenbush, J, Puryear, R, Powers, M, Cheng, T, Ludwig, EH, Sharma, AM, Hata, A, Jeunemaitre, X, Lalouel, JM A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest, 99(7), 1786-97, 1997.
- Williams, CS, Smalley, W, DuBois, RN Aspirin use and potential mechanisms for colorectal cancer prevention. J Clin Invest, 100(6), 1325-9, 1997.
- Zhang, T, Nanney, LB, Peeler, MO, Williams, CS, Lamps, L, Heppner, KJ, DuBois, RN, Beauchamp, RD Decreased transforming growth factor beta type II receptor expression in intestinal adenomas from Min/+ mice is associated with increased cyclin D1 and cyclin-dependent kinase 4 expression. Cancer Res, 57(9), 1638-43, 1997.
- Williams, CS, Luongo, C, Radhika, A, Zhang, T, Lamps, LW, Nanney, LB, Beauchamp, RD, DuBois, RN Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology, 111(4), 1134-40, 1996.
- DuBois, RN, Eberhart, CF, Williams, CS Introduction to eicosanoids and the gastroenteric tract. Gastroenterol Clin North Am, 25(2), 267-77, 1996.
- Hunt, SC, Williams, CS, Sharma, AM, Inoue, I, Williams, RR, Lalouel, JM Lack of linkage between the endothelial nitric oxide synthase gene and hypertension. J Hum Hypertens, 10(1), 27-30, 1996.
- Williams, CS, DuBois, RN Prostaglandin endoperoxide synthase: why two isoforms. Am J Physiol, 270(3 Pt 1), G393-400, 1996.
- Jeunemaitre, X, Soubrier, F, Kotelevtsev, YV, Lifton, RP, Williams, CS, Charru, A, Hunt, SC, Hopkins, PN, Williams, RR, Lalouel, JM Molecular basis of human hypertension: role of angiotensinogen. Cell, 71(1), 169-80, 1992.