Robert J. Coffey, M.D.
Ingram Professor of Cancer Research
Professor of Medicine (Gastroenterology, Hepatology and Nutrition)
Professor of Cell and Developmental Biology
2213 Garland Avenue
10415 MRB IV -0441
Nashville, TN 37232
The Coffey lab seeks a comprehensive understanding of the role of EGF receptor (EGFR) and its ligands in epithelial cell growth, differentiation and neoplasia. In vitro, we study spatial compartmentalization of key components of the EGFR axis in the context of polarized epithelial cells. For example, two critical EGFR ligands, TGF-alpha and amphiregulin, are both delivered exclusively to the basolateral surface, cleaved by TACE/ADAM-17, but then interact with basolateral EGFRs in very different ways. Naked 2 and MAGI-3 have been identified recently as two proteins that bind the cytoplasmic tail of TGF-alpha and play important roles in the fidelity (former) and efficiency (latter) of TGF-alphai??s trafficking to the basolateral surface. Naked2 coats exocytic vesicles that contain TGF-alpha and escorts these vesicles to the basolateral surface where they dock and fuse in a Naked2 myristoylation-dependent manner. Naked2 vesicles have been isolated, 389 proteins have been identified by use of fluorescence-activated vesicle sorting (FAVS) and LC/MS-MS.
In vivo, mouse models of GI neoplasia are being developed and utilized by Vanderbilti??s involvement in the NCI-sponsored Mouse Models of Human Cancers Consortium (of which Dr. Coffey is PI). Innovative therapeutic strategies to disrupt the EGFR axis (ligand cleavage, ligand uptake by receptor, receptor tyrosine kinase activity) in GI neoplasia are fashioned in tissue culture models, refined in mouse models and advanced to clinical trials. A recent example is the successful treatment of a patient with a premalignant disorder of the stomach, Mi??ni??trieri??s disease with EGFR blockade (Erbitux). These efforts have been greatly accelerated by Vanderbilt receiving a 5-year, $13 million GI Special Program of Research Excellence (SPORE) award from the NCI to study colorectal cancer; Dr. Coffey is PI. A major effort is to identify the colonic stem cell using microarray and proteomic profiling. Dr. Coffey also directs the recently-formed VUMC Epithelial Biology Center.
- Powell, AE, Wang, Y, Li, Y, Poulin, EJ, Means, AL, Washington, MK, Higginbotham, JN, Juchheim, A, Prasad, N, Levy, SE, Guo, Y, Shyr, Y, Aronow, BJ, Haigis, KM, Franklin, JL, Coffey, RJ The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell, 149(1), 146-58, 2012.
- Higginbotham, JN, Demory Beckler, M, Gephart, JD, Franklin, JL, Bogatcheva, G, Kremers, GJ, Piston, DW, Ayers, GD, McConnell, RE, Tyska, MJ, Coffey, RJ Amphiregulin exosomes increase cancer cell invasion. Curr Biol, 21(9), 779-86, 2011.
- Hu, T, Li, C, Cao, Z, Van Raay, TJ, Smith, JG, Willert, K, Solnica-Krezel, L, Coffey, RJ Myristoylated Naked2 antagonizes Wnt-beta-catenin activity by degrading Dishevelled-1 at the plasma membrane. J Biol Chem, 285(18), 13561-8, 2010.
- Fiske WH, Tanksley J, Nam KT, Goldenring JR, Slebos RJC, Liebler DC, Abtahi AM, La Fleur B, Ayers JD, Lind CD, Washington MK and Coffey RJ Efficacy of cetuximab in the treatment of M¿¿n¿¿trier¿¿¿s disease. Science Translational Medicine , 2009.
- Ding W, Li C, Hu T, Graves-Deal R, Fotia AB, Weissman AM and Coffey RJ EGF receptor-independent action of TGF-alpha protects Naked2 from AO7-mediated ubiquitylation and proteasomal degradation. Proc Natl Acad Sci U S A , (105), 13433-134338, 2008.
- Manning, HC, Merchant, NB, Foutch, AC, Virostko, JM, Wyatt, SK, Shah, C, McKinley, ET, Xie, J, Mutic, NJ, Washington, MK, Lafleur, B, Tantawy, MN, Peterson, TE, Ansari, MS, Baldwin, RM, Rothenberg, ML, Bornhop, DJ, Gore, JC, Coffey, RJ Molecular Imaging of Therapeutic Response to Epidermal Growth Factor Receptor Blockade in Colorectal Cancer. Clin Cancer Res, 14(22), 7413-7422, 2008.
- Merchant, NB, Voskresensky, I, Rogers, CM, Lafleur, B, Dempsey, PJ, Graves-Deal, R, Revetta, F, Foutch, AC, Rothenberg, ML, Washington, MK, Coffey, RJ TACE/ADAM-17: a component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer. Clin Cancer Res, 14(4), 1182-91, 2008.
- Cao, Z, Li, C, Higginbotham, JN, Franklin, JL, Tabb, DL, Graves-Deal, R, Hill, S, Cheek, K, Jerome, WG, Lapierre, LA, Goldenring, JR, Ham, AJ, Coffey, RJ Use of fluorescence-activated vesicle sorting for isolation of Naked2-associated, basolaterally-targeted exocytic vesicles for proteomic analysis. Mol Cell Proteomics, 7(9), 1651-67, 2008.
- Rothenberg, ML, LaFleur, B, Levy, DE, Washington, MK, Morgan-Meadows, SL, Ramanathan, RK, Berlin, JD, Benson, AB, Coffey, RJ Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol, 23(36), 9265-74, 2005.
- Li, C, Franklin, JL, Graves-Deal, R, Jerome, WG, Cao, Z, Coffey, RJ Myristoylated Naked2 escorts transforming growth factor alpha to the basolateral plasma membrane of polarized epithelial cells. Proc Natl Acad Sci U S A, 101(15), 5571-6, 2004.
- Roberts, RB, Min, L, Washington, MK, Olsen, SJ, Settle, SH, Coffey, RJ, Threadgill, DW Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc Natl Acad Sci U S A, 99(3), 1521-6, 2002.
- Burdick, JS, Chung, E, Tanner, G, Sun, M, Paciga, JE, Cheng, JQ, Washington, K, Goldenring, JR, Coffey, RJ Treatment of MÃ©nÃ©trier''s disease with a monoclonal antibody against the epidermal growth factor receptor. N Engl J Med, 343(23), 1697-701, 2000.
- Dempsey, PJ, Coffey, RJ Basolateral targeting and efficient consumption of transforming growth factor-alpha when expressed in Madin-Darby canine kidney cells. J Biol Chem, 269(24), 16878-89, 1994.
- Matsui, Y, Halter, SA, Holt, JT, Hogan, BL, Coffey, RJ Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice. Cell, 61(6), 1147-55, 1990.
- Coffey, RJ, Derynck, R, Wilcox, JN, Bringman, TS, Goustin, AS, Moses, HL, Pittelkow, MR Production and auto-induction of transforming growth factor-alpha in human keratinocytes. Nature, 328(6133), 817-20, 1987.