The Brugge laboratory is investigating the cellular processes and pathways that are involved in normal morphogenesis of epithelial tissues and the initiation and progression of epithelial tumors. Currently, most of our studies involve investigations relating to breast cancer. One of the major approaches that we use to investigate these processes involves culturing breast epithelial cells reconstituted basement membrane gels which allows the cells to organize into 3-dimensional structures that resemble the hollow, spherical glandular units of the breast. This culture system allows us to model events that control the proliferation, survival and migration of normal epithelial cells, to identify cellular genes that allow escape from these controls and induce phenotypic changes resembling those associated with tumor progression, and to elucidate the mechanisms responsible for these events. One of the major focuses of this project involves studies of cell death processes that are critically involved in the formation of a lumen in the spheroid, gland-like breast epithelial structures and how oncogenes escape these death processes to allow filling of the luminal space. One of the hallmarks of early-stage carcinomas filling of the lumen. We have found that multiple processes contribute to the death or clearance of cells from the lumen, including apoptosis, metabolic impairment and autophagy, and intercalation into the outer cell monolayer. Our studies indicate that the induction of apoptosis and autophagy may be a consequence of lack of matrix protein deposition by the inner cells of the acinar structures, so we are investigating how matrix proteins regulate apoptosis and metabolic activity and how oncogenes suppress apoptosis and allow rescue from metabolic impairment. Lastly, we have identified a novel, non-apoptotic mechanism of cell death that involves invasion of one cell into the other, followed by lysosomal degradation of the invading cell. We are exploring the role of this process in tumor surveillance and other physiological processes. Another major focus is on cellular pathways that regulate the aberrant migration and invasion of tumor cells. We are carrying out siRNA screens to identify genes that inhibit or enhance cell migration and invasion, investigating the mechanisms responsible for these events, and establishing whether these pathways are involved in invasion in vivo.