Joan S. Brugge
We are interested in elucidating the cellular processes and pathways that are involved in the initiation and progression of epithelial tumors. Currently, most of our studies involve investigations relating to breast cancer; however we have recently initiated studies of ovarian tumors as well. One of the major approaches that we use to investigate these processes involves culturing breast epithelial cells 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 within these structures, 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. We are also investigating how matrix contributes to drug resistance by regulating the upregulation of survival programs.
Another major focus is on cellular pathways that regulate the aberrant migration and invasion of tumor cells. We have carried out siRNA screens to identify genes that inhibit or enhance cell migration and invasion and are investigating the mechanisms responsible for these events and establishing whether these pathways are involved in invasion in vivo. A major focus is on proteins that regulate cell-cell adhesion and collective migration. We are also investigating pathways that regulate tumor metastasis.
Other studies involve investigations of cellular pathways that control normal differentiation of breast epithelial cells in order to understand the contribution of factors and pathways that regulate these events in tumorigenesis.
Building C1, Room 513A
240 Longwood Avenue
Boston, MA 02115
Assistant: Kerry Mojica, 617-432-3973