Cell polarity and cell adhesion in mammalian development and cancer

Our laboratory studies the mechanisms and significance of cell polarity and cell adhesion in normal mammalian development and cancer. In addition, we have a significant interest in the mechanisms responsible for initiation and progression of human prostate cancer. We believe that it is important to study cells in their normal microenvironment. Thus, our major model system is mouse, and our primary approach is generation and characterization of genetically modified mice. While this approach takes a lot of time and consumes a significant part of our grant money, we believe that it provides us with information that is most relevant to understanding the critical causal events that are responsible for human diseases. Our secondary approach is to use cells in culture to model the phenotypes that we see in our mutant mice and dissect the molecular mechanisms responsible for these phenotypes. This combination of in vivo genetic and ex vivo cell biology approaches has enabled us to identify and analyze the causal events responsible for several cancer types and a variety of developmental disorders. In the course of these studies, we have uncovered novel mechanisms responsible for tumor initiation and metastasis in prostate and skin cancer. We also found the mechanisms responsible for the number of developmental disorders including periventricular heterotopia, hydrocephalus, lung emphysema, kidney cysts and placental malformations. These studies resulted in research papers in such journals as Science, Science Signaling, Cancer Cell, Dev Cell, Genes Dev, PNAS, J Cell Biol, Mol Cell Biol, J Cell Science and many others. Presently, our laboratory is pursuing research in three major directions:

1. We are trying to understand how stem and progenitor cells use intercellular adhesion structures to obtain information about their cellular microenvironment and translate this information into critical decisions concerning cell proliferation, differentiation and programmed cell death. These studies concentrate on the role and mechanisms of cell-cell adhesion structures called Adherens Junctions and the protein α-catenin. We discovered that α-catenin functions as a tumor suppressor in squamous cell carcinoma, and we have begun to identify the mechanisms responsible for this function.

2. We are studying the mechanisms responsible for asymmetric cell division of stem and progenitor cells that help to ensure both the maintenance of pluripotent stem cell population and normal cell differentiation. We believe that the failure of these mechanisms is ultimately responsible for cancer. These studies concentrate on the role and mechanisms of basolateral cell polarity proteins Lgl1, Lgl2 and Dlg5. We determined that Lgls and Dlg5 are responsible for several developmental disorders, and we made significant advances in understanding the mechanisms of their function.

3. We are studying the causal mechanisms responsible for initiation and progression of human prostate cancer. To determine causality, we use mice to model the genetic and epigenetic changes identified in human prostate tumors. When the causal event is identified, we analyze the cellular and molecular mechanisms responsible. These studies concentrate on the role and mechanisms of cell-surface serine protease Hepsin and the ETS-family transcription factor ERG. We found that hepsin drives prostate cancer progression and metastasis and ERG is involved in long-term cancer initiation. We made significant progress in understanding the molecular mechanisms of Hepsin and ERG in prostate cancer. In addition, we developed and characterized a small molecule Hepsin inhibitor, which is now undergoing an animal prostate-cancer trial.