Photo of Senthil K Muthuswamy,  PhD

Senthil K Muthuswamy, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 735-2238


smuthusw@bidmc.harvard.edu

Senthil K Muthuswamy, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Associate Professor, Medicine, Harvard Medical School
  • Director of Cell Biology at Cancer Center, Medicine, Beth Israel Deaconess Medical Center

DF/HCC PROGRAM AFFILIATION

Research Abstract

Over the past 15 years studies from my laboratory have led to the development of three-dimensional culture methods for modeling carcinoma and identify cell polarity proteins as a new class of molecules regulating cancer biology.

The 3D culture model we developed for breast epithelia (Nat Cell Biol,(NCB) 2001; Cell, 2002) has opened a new way of thinking and investigating biology of cancer cells. In addition to understanding mechanisms of cell invasion, cell proliferation and death in a 3D tissue-like context, the 3D culture method has impacted drug development and understanding drug resistance mechanisms. We have used it to identify, for the first time, cell polarity proteins such as PARD6, PARD3 and SCRIB, as critical regulators of cell death, cell proliferation and metastasis either by themselves or in cooperation with oncogenes such as ERBB2 and MYC (NCB, 2006; Cell, 2008; NCB, 2013). Recently, we reported that mislocalization of the cell polarity SCRIB from cell-cell junctions is sufficient to initiate mammary tumorigenesis, identifying changes in subcellular localization of polarity proteins as a novel regulator of cancer. Our unpublished studies have identified an unexpected role for SCRIB in macrophages, where SCRIB polarizes to phagosomes and regulates generation of reactive oxygen species involved in killing bacteria and regulating M1 versus M2 macrophage polarization and inflammation. Thus, studies from my laboratory have opened the field of cell polarity biology to cancer researchers and those interested in cell signaling, cell migration, metastasis and stemness.

Our recent pancreas 3D culture 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, we demonstrate using 3D platform that primary patient-derived pancreas tumor cells grow as tumor-organoids. These organoids preserve physiological features of the original tumor and are a powerful platform for identifying personalized treatment options for cancer patients and for discovering new drug targets.

Lastly, as a citizen of science, I take keen interest in playing an active role in mentoring next generation of scientists and engaging in administrative and professional activities to positively impact the scientific community.

Publications

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  • Muthuswamy SK. Bringing together the organoid field: from early beginnings to the road ahead. Development 2017; 144:963-967. PubMed
  • 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 2006; 8:1235-45.
  • Zhan L, Rosenberg A, Bergami KC, Yu M, Zuan Z, Jaffe AB, Allred C, Muthuswamy S.K. . Deregulation of Scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma Cell 2008; 135:865-78.
  • Xue, B, Krishnamurthy, K, Allred, CA, Muthuswamy, SK. Loss of Par3 promotes breast cancer metastasis by compromising cell-cell cohesion. Nat Cell Biol 2013; 15:189-200.
  • 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. . Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell– and patient-derived tumor organoids. Nat Med 2015; 21:1364-71.