A major focus of the Coffey lab is the trafficking of the EGF receptor (EGFR) ligands in polarized epithelial cells. Highlights include identification of Naked2 (NKD2) as a critical regulator of basolateral trafficking of TGFA. NKD2 recognizes basolateral sorting determinants in the cytoplasmic tail of TGFA; it coats TGFA-containing exocytic vesicles and directs them to the basolateral corner of polarized epithelial cells, where they dock and fuse in a NKD2 myristoylation-dependent manner. NKD2 antagonizes Wnt-beta-catenin signaling, providing a point of convergence between EGFR and Wnt signaling. This work has led to the development of FAVS (fluorescence-activated vesicle sorting) as a flow cytometry-based strategy to isolate and characterize cellular organelles and the discovery of a new mode of EGFR ligand signaling via exosomes. The lab has recently found that mistrafficking of epiregulin from the basolateral to the apical surface is a highly transforming event. The lab has special expertise in culturing cells in a 3D environment, and recently developed a novel 3D system to study colorectal cancer.
A recent important advance from the Coffey lab is that Lrig1, an EGFR negative regulator, marks a distinct population of largely quiescent intestinal stem cells and functions as a tumor suppressor. A highly tractable, inducible mouse model of colon cancer has been developed using Lrig1-CreERT2; Apcflox/+ mice. Another important advance is that mutant KRAS affects the protein and RNA composition (both miRNA and lncRNA) and behavior of exosomes.
Coffey remains clinically active. Work from his lab has implicated overproduction of TGFA and heightened EGFR activity in the pathogenesis of Ménétrier’s disease, a rare but debilitating premalignant gastropathy. He and his colleagues have identified cetuximab, an EGFR neutralizing monoclonal antibody, as the first effective medical treatment for this disease.
Coffey also directs Vanderbilt’s Epithelial Biology Center, a trans-departmental initiative to study epithelial polarity, vesicle trafficking and intestinal stem cells. He directs Vanderbilt’s Specialized Program of Research Excellence (SPORE) in GI cancer that focuses on colorectal cancer; this multi-investigator grant is supported by the National Cancer Institute and was recently renewed for its 3d cycle of funding. In addition to the SPORE, present funding includes 4 R01s, a U19 and VA Merit Award.