Note that the citation numbers refer to the papers listed on the "Publications" page.
OVERVIEW – My research group studies the Epidermal Growth Factor (EGF) family of peptide hormones and their receptors, the ErbB family of receptor tyrosine kinases. This network plays a significant role in regulating the proliferation and differentiation of epithelial cells. Moreover, deregulated signaling by this network is a causative event in many human tumors, and contributes to increased tumor cell invasiveness, metastatic potential, and chemoresistance. Consequently, our group studies this signaling network with the ultimate goal being the development of novel cancer diagnostic and treatment strategies.
ERBB4 AND EPITHELIAL TUMORS - ErbB4 expression is lost in many epithelial tumors, suggesting that ErbB4 is a tumor suppressor in these tissues. Indeed, a constitutively active, ligand independent ErbB4 mutant inhibits colony formation on plastic by human breast, pancreatic, and prostate tumor cell lines [19, 25, 26, 41, 50]. However, other data indicate that ErbB4 is coupled to tumor cell proliferation, motility, and invasiveness [41, 44]. We are using various expression systems, analytical approaches, ErbB4 ligands, and ErbB4 mutants to characterize ErbB4 coupling to tumor suppression and malignant phenotypes. We are are focused on deciphering the mechanisms by which ErbB4 can be coupled to these divergent responses and on developing strategies for treating ErbB4-dependent tumors [13, 25, 26, 31, 32, 41, 43, 44, 46, 55].
EGF FAMILY HORMONES - In collaboration with Mark Lemmon (University of Pennsylvania), Kathryn Ferguson (University of Pennsylvania), Stephen Ethier (Wayne State University), John Foley (Indiana University), Anne Lykkesfeldt (Danish Cancer Institute), James Leary (Purdue University), Laurie Parker (Purdue University) and Claudio Aguilar (Purdue University), we are characterizing the biological activities of EGF family hormones and we are identifying factors that regulate the affinity, potency, and efficacy of these peptide growth factors [13, 17, 20, 21, 23, 24, 29, 30, 32, 34, 36, 39, 40, 42, 43, 44, 45, 46, 47, 51]. We are particularly interested in elucidating the roles that EGFR and its ligands play in tumor cell colonization of the bone. We are also interested in elucidating the structural features of EGF family hormones that are responsible for differences in affinity, potency, and efficacy. Recently we have discovered that some EGF family hormones can antagonize the activity of other EGF family hormones and that single amino acid substitutions can be sufficient to change an agonist to an antagonist and vice versa. Thus, these studies have the potential to yield new cancer therapies.
TARGETED TUMOR IMAGING AGENTS - In collaboration with Henry VanBrocklin (UCSF) and Julie Sutcliffe-Golden (UC-Davis), we are investigating EGFR ligands as possible functional targeted tumor imaging agents. EGFR ligands under investigation include small molecule inhibitors, oligopeptides, and EGF family hormones and hormone mutants . Such agents have the potential to selectively image aggressive primary tumors and their metastases.
EGFR AND HUMAN MALIGNANCIES - In collaboration with Jeffrey Settleman (Genentech) and John Foley (Indiana University), we are investigating the mechanisms by which EGFR mutants contribute to chemosensitivity and chemoresistance in non-small-cell lung carcinoma (NSCLC) [27, 28, 33]. We are also investigating the mechanisms by which these EGFR mutants contribute to tumor cell invasion and metastsasis. We are focusing on the role that ligand-induced EGFR heterodimerization with other ErbB receptors may play in these processes. Finally, we are investigating the roles that ligand-induced EGFR signaling plays in the colonization of bone by lung and breast tumor cells [29, 39, 40].
EGFR AS SIGNAL INTEGRATOR - In collaboration with Val Watts and Julia Chester (Purdue University), we are investigating whether EGFR mediates the effects of dopamine and alcohol on breast cells [35, 38]. Such studies may elucidate the mechanisms by which Parkinson's disease patients and individuals suffering from alcoholism exhibit an elevated risk of developing breast cancer. Such studies may also result in strategies for managing this risk.