Members of transforming growth factor beta (TGFß) family play central roles in animal development, animal cell physiology and human disease. The overall research goals of the laboratory are (1) to elucidate the functional and molecular mechanisms underlying specific TGFß family signaling pathways, (2) to understand how disregulation of these pathways causes disease in humans, and (3) to apply our functional and mechanistic insights to identify protein-based inhibitors that target these pathways for therapeutic purposes.
We use several parallel approaches to accomplish our goals. We apply molecular methods, including cloning, protein expression, protein purification, Surface Plasmon Resonance and X-ray crystallography to study the mechanism of action of individual TGFß family ligands and their regulators. We probe the effect of TGFß family ligands and their regulators using a variety of cell based assays and genomic methods. We collaborate to test inhibitors with therapeutic potential in animal models. Current projects include the TGFß family ligand Nodal and its regulators Cerberus and Lefty, as well as Activins and their regulators.
Project 1: Nodal and Cerberus:
Nodal is an essential regulator of vertebrate embryonic development that that is largely absent from adult tissues. However, recent studies showed that Nodal is re-expressed in some metastatic carcinomas, and that Nodal promotes cancer progression (Figure 1). Nodal inhibitors could therefore be used to treat cancers where Nodal plays a role. Using molecular approaches our laboratory showed that the embryonic Nodal signaling antagonist Cerberus is a Nodal inhibitor (Figure 2). Cerberus binds Nodal with high affinity and specificity, blocks binding of Nodal to its receptors and co-receptors, and inhibits Nodal signaling (Figure 3). Using cancer cell assays, our laboratory demonstrated that Cerberus profoundly suppresses aggressive phenotypes in certain human breast cancer cell lines, suggesting that Cerberus could work as therapeutic in breast cancer treatment (Movie). Our laboratory seeks to fully elucidate the molecular and cellular mechanism of Cerberus action underlying the breast cancer cell phenotypes and to test Cerberus in appropriate human breast cancer metastasis models.