Cell polarity, morphogenesis and differentiation during development and disease
Cancer is a progressive disease. Although we are not entirely certain how it originates, we now know that accumulation of mutations, increase in cell proliferation, decrease in cell death and changes in cell differentiation status are associated with progression of disease. While the pathways that drive cell proliferation and cell survival are increasingly becoming clear, less is understood about how differentiation status is altered during cancer progression.
Cell polarity proteins regulate asymmetric distribution of proteins within cells during tissue morphogenesis and during differentiation of progenitor cells in flies and worms. Very little is known about the role cell polarity proteins play during morphogenesis and differentiation in mammals. Furthermore, the role cell polarity proteins play during initiation and progression of cancer is poorly understood. Research in our laboratory is aimed at understanding how cell polarity proteins regulate differentiation of stem and progenitor cells, regulate three-dimensional tissue morphogenesis and how these processes regulate initiation and progression of cancer.
Recent studies from our laboratory have yielded surprising insights into the role cell polarity proteins play in cancer. We find that oncogenic receptor tyrosine kinase ErbB2/HER2 interacts with Par6 polarity protein to disrupt apical-basal polarity and morphogensis during transformation of polarized breast epithelial 3D acini. The ability of ErbB2/HER2 to disrupt cell polarity is independent it’s ability to induce cell proliferation suggesting that pathways that regulate cell polarity and morphogenesis can be uncoupled from pathways that induce cell proliferation. More recently, we discovered that disruption of Scribble polarity protein deregulates morphogenesis of mammary epithelial cells in culture and initiates carcinoma in animal models. These observations demonstrate that changes in cell polarity proteins can function either as an initiating or as a cooperating event during the genesis of carcinoma. Thus, cell polarity proteins are a novel, unexplored class of targets that can be exploited for diagnosis and treatment of carcinoma.
Research in our laboratory is broadly focused on investigating how cell polarity proteins regulate normal development and initiation and progression of cancer. We are interested in: 1) identifying polarity pathways that are altered in breast and other cancers and determine their clinical relevance; 2) determining how polarity pathway controls differentiation of stem and progenitor cells; 3) developing mouse models with alterations in polarity genes to study both normal development and cancer progression; 4) conducting proteomics and genetic screens to identify novel targets for the altered/rewired polarity pathways in cancer cells.
Dr. Miller is no longer available for graduate student supervision.
Selected References:
Link to Pubmed Publications- Huang, L., Muthuswamy, S.K. Polarity protein alterations in carcinoma: a focus on emerging roles for polarity regulators. Curr Opin Genet Dev. 20(1):41-50, 2010. NIHMS171874
- Xiang, B., Chatti, K., Qiu, H., Lakshmi, B., Krasnitz, A., Hicks, J., Yu, M., Miller, W.T., and Muthuswamy, S.K., Brk is coamplified with ErbB2 to promote proliferation in breast cancer. Proc Natl Acad Sci U S A, 105(34): p. 12463-8, 2008. PMCID: PMC2527934
- Zhan, L., Rosenberg, A., Bergami, K.C., Yu, M., Xuan, Z., Jaffe, A.B., Allred, C., and Muthuswamy, S.K., Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell, 135(5): p. 865-78, 2008. NIHMS81991
- Aranda, V., Haire, T., Nolan, M.E., Calarco, J.P., Rosenberg, A.Z., Fawcett, J.P., Pawson, T., and Muthuswamy, S.K., Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat Cell Biol, 8(11): p. 1235-45, 2006.
- Muthuswamy, S.K., Li, D., Lelivere, S., Bissell, M. and Brugge, J.S. (2001). ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat. Cell Biol 3: 785-792.
