Senthil K. Muthuswamy
Ph.D., McMaster University, 1995
Understanding cancer initiation using three-dimensional epithelial structures
Current therapeutic strategies are mostly aimed at controlling malignant stage cancers. Although this strategy helps patients by extending their lifespan, in the end the patients often succumb to the disease. However, if we could treat or control precancerous lesions so that they never progress to form malignant cancers, patients can be maintained tumor-free. The bottleneck in accomplishing this goal is the almost complete lack of understanding of the mechanisms that regulate development and progression of precancerous lesions.
Features of precancerous lesions include an increase in cell proliferation and loss of normal tissue architecture. While we are making progress in understanding how cell proliferation control is deregulated in cancer, the molecular mechanisms by which tissue architecture is lost is poorly understood. This is, in part, because traditional laboratory methods employ cells grown on plastic dishes, and do not recreate the normal 3-D organization of epithelial cells observed in organs in vivo and hence, are not suited to investigate changes in 3-D tissue architecture.
We bridge this gap by the use of an organotypic, 3-D cell culture method that recreates the epithelial organization seen in breast tissue. Using the 3-D culture method we have recently discovered that oncogenes such as HER2/ErbB2 disrupt epithelial organization by deregulating pathways that maintain normal polarity/architecture of epithelial cells. Our current efforts are focused on addressing questions such as: 1) How do polarity pathways modify oncogene induced transformation? 2) Are changes in polarity pathways novel predictive biomarkers and drug targets for early lesions?
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Aranda, V., Haire, T., Nolan, M.E., Calarco, J.P., Rosenberg, A.Z., Fawcett, J.P., Pawson, T., and Muthuswamy, S.K. 2006. Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat. Cell Biol. 8: 1235–1245.
Wang, S.E., Narasanna, A., Perez-Torres, M., Xiang, B., Wu, F.Y., Yang, S., Carpenter, G., Gazdar, A.F., Muthuswamy, S.K., and Arteaga, C.L. 2006. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10: 25–38.
Zhan, L., Xiang, B., and Muthuswamy, S.K. 2006. Controlled activation of ErbB1/ErbB2 heterodimers promote invasion of three-dimensional organized epithelia in an ErbB1-dependent manner: implications for progression of ErbB2-overexpressing tumors. Cancer Res. 66: 5201–5208.
Xiang, B., and Muthuswamy, S.K. 2006. Using three-dimensional acinar structures for molecular and cell biological assays. Methods Enzymol. 406: 692–701.