Joan S. Brugge

Department of Cell Biology
Harvard Medical School
Building C, Room 513b
240 Longwood Ave.
Boston MA 02115
Tel: (617) 432-3974
Fax: (617) 432-3969
Email: joan_brugge@hms.harvard.edu
Web Page: The Brugge Lab Page
12 postdoctoral fellows, 5 graduate students

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. 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. 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.

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.

References:

• Debnath, J, Mills, KR, Collins NL, Reginato MJ, Muthuswamy SK, and Brugge JS. The role of apoptosis in creating and maintaining luminal Space within normal and oncogene-expressing mammary acini. Cell, 111:29-40(2002).
• Mailleux, A.A. Overholtzer, M., Schmelzle,T. Bouillet, P., Strasser. A., and Brugge, J.S. BIM Regulates Apoptosis During Mammary Ductal Morphogenesis and its Absence Reveals Alternative Cell Death Mechanisms. Developmental Cell 12, 221-134. 2007.
• Overholtzer M, Mailleux AA, Mouneimne G, Normand G, Schnitt SJ, King RW, Cibas ES, Brugge JS. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131 (5): 966-79, 2007.
• Simpson, KJ, Selfors LM, Bui J, Reynolds A, Leake D, Khvorova A and Brugge JS. Identification of genes that regulate epithelial cell migration using an siRNA screening approach. Nature Cell Biology, in press.