My laboratory is interested in understanding how basic cellular processes perturbed by cancer genes produce the histological changes observed in epithelial cancers. Using an in vitro three-dimensional (3D) epithelial culture model to examine the biological activities of cancer genes, we discovered that isolated events like increasing proliferation or decreasing apoptosis do not disrupt epithelial architecture; rather, combinations of events are required for phenotypic changes associated with cancer such as filling of the lumen.
More recently, we found that autophagy also impacts on epithelial homeostasis in this 3D model. Autophagy is a fundamental catabolic process in which the cytoplasm and organelles of a cell are sequestered within double membrane vacuoles, called autophagosomes, and subsequently delivered to the lysosome for degradation (i.e. a cell "eats itself"). In mammalian cells, autophagy primarily functions as a cytoprotective response to nutrient deprivation or stress; however, when excessive autophagy occurs in a cell, programmed cell death ensues. My laboratory now wishes to understand how autophagy contributes to both epithelial homeostasis and cancer using the 3D model and other in vitro and in vivo models. Our three main goals are: 1) investigate the role of autophagy in epithelial cell fate and oncogenic transformation; 2) examine the role of autophagy in chemotherapeutic response in cancer cells; and 3) investigate the role of autophagy in tissue homeostasis and tumor formation in vivo . |
J. Debnath , Baehrecke, E., and Kroemer, G. (2005). Does Autophagy Contribute to Programmed Cell Death? Autophagy . 1(2).
K. Mills, Reginato, M., Debnath, J. , Queenan, B., and Brugge, J. (2004). TRAIL Is Required For Induction of Autophagy During Lumen Formation In Vitro. Proc. Nat. Acad. Sci. 101:3438-43.
J. Debnath , Walker, S. and Brugge, J. (2003). Akt Activation Disrupts Mammary Acinar Architecture and Enhances Proliferation In An mTOR Dependent Manner. J. Cell Biol. 163: 315-326.
J. Debnath , Mills, K., Collins, N., Reginato, M., Muthuswamy, S., and Brugge, J. (2002). The Role Of Apoptosis In Creating and Maintaining Luminal Space Within Normal and Oncogene-Expressing Mammary Acini. Cell . 111: 29-40.
information last updated May 2005
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Biomedical Sciences (BMS) Graduate Program
