BBS Faculty Member - Senthil Muthuswamy

Senthil Muthuswamy

Department of Medicine

Beth Israel Deaconess Medical Center
CLS Building, Room 445
3 Blackfan Circle
Boston, MA 02115
Tel: 617-735-2238
Email: smuthusw@bidmc.harvard.edu
Visit my lab page here.



Over the past 15 years studies from my laboratory have led to the development of methods for growing cancer cells in three-dimensional culture and to the identification of proteins that regulate cell structure and intracellular asymmetry, referred to as cell polarity, as a new class of molecules regulating the biology of cancer.

In 2001, we reported the development of a 3D cell culture model for breast epithelial cells (Nat Cell Biol, (NCB) 2001; Cell, 2002), which has opened new ways for researchers to investigate mechanisms in cancer cell biology including topics related to cell invasion, cell proliferation, cell death and drug resistance. In our own laboratory, we have used 3D culture methods to identify cell polarity proteins, such as PARD6, PARD3 and SCRIB, as critical regulators of cell death, cell proliferation and metastasis in cancer cells (NCB, 2006; Cell, 2008; NCB, 2013). In addition, we find that mislocalization of the cell polarity protein SCRIB from cell-cell junctions is sufficient to initiate mammary tumorigenesis, identifying simple changes in subcellular localization of polarity proteins as a regulator of cancer biology. Recently, we identified an unexpected role for SCRIB in macrophages. SCRIB interacts with the NAPH oxidase complex to regulate production of reactive oxygen species involved in M1 polarization, inflammation and bacterial killing. These and other studies from our laboratory have identified cell polarity proteins as regulators of cell biological processes involved in cancer, cell signaling, cell migration, metastasis and stemness.

During the past few years, we have begun to expand our expertise in 3D culture towards developing organoid models for growing patient-derived tumor cells. Our recently reported pancreas organoid model (highlighted as Notable Advance of 2015 by Nat. Med) defines new ways to generate ductal and acinar (exocrine) cells from pluripotent human stem cells. This opens door, for the first time, to model exocrine pancreatic diseases such as pancreatitis and pancreatic cancer in culture. Furthermore, the method can be used to generate patient tumor derived organoid (PDO) cultures with high efficiency. These organoids resemble mini-tumors in a dish and preserve many physiological features of the matched patient tumor. We believe that PDO cultures have the potential to serve as a powerful platform for identifying personalized treatment options for cancer patients and for discovering new drug targets.

In summary, research initiatives in my laboratory are aimed at developing new culture methods both for investigating the role cell polarity proteins play in modulating cancer cell biology and for translational cancer research. As a citizen of science, I take keen interest in playing an active role in mentoring next generation of scientists.



Last Update: 12/7/2016



Publications

For a complete listing of publications click here.

 


 

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(11): p. 1235-45.

Zhan L, Rosenberg A, Bergami KC, Yu M, Zuan Z, Jaffe AB, Allred C,
Muthuswamy S.K. (2008) Deregulation of Scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell, 135(5):865-78.

Xue, B, Krishnamurthy, K, Allred, CA,
Muthuswamy, SK. (2013) Loss of Par3 promotes breast cancer metastasis by compromising cell-cell cohesion. Nat Cell Biol.,15(2):189-200.

Huang, L., Holtzinger A., Jagan, I., BeGora, M., Lohse, I., Ngai, N., Nostro, C., Wang, R., Muthuswamy, L.B., Crawford, H.C., Cheryl Arrowsmith, C., Kalloger, S.E., Renouf, D.J., Connor, A., Cleary, S., Schaeffer, D.F., Roehrl, M., Tsao, M., Gallinger, S., Keller, G., and
Muthuswamy, S.K. (2015) Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell– and patient-derived tumor organoids. Nat Med., 21(11):1364-71

Zheng, W, Umitsu, M, Jagan, I, Charles W. Tran, CW, Ishiyama, N, BeGora, M, Araki, K, Pamela S. Ohashi, PS, Ikura, M and
Muthuswamy, SK. (2016) An interaction between SCRIBBLE and NADPH oxidase complex controls M1 macrophage polarization and function. Nat. Cell. Biol. In Press.



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