Senthil K. Muthuswamy, Ph.D.

Senior Investigator

Laboratory of Cancer Biology and Genetics

NCI/CCR

Building 37, Room 4068A
Bethesda, MD 20892

301-480-8474

senthil.muthuswamy@nih.gov

Research Topics

In 2001, we developed a 3D culture platform to grow a human breast epithelial cell line, MCF-10A, as polarized acinar structures and used it to investigate how 3D cell architecture impacts transformation by the oncogene HER2/ErbB2. These studies provided an unexpected insight into the role of 3D cell architecture and cell polarity in cancer biology. Expanding on this insight, we developed conditions to grow pancreatic tumor as tumor organoid cultures. We demonstrated that the tumor organoids are highly effective in modeling in vivo and clinical drug responses, validating their utility as clinically relevant research platforms. Our ongoing research program is designed to develop new 3D culture/organoids experimental platforms and use them for understanding mechanisms regulating tumor histoarchitecture, metastasis, response to therapeutic drugs, and personalization of drug treatment for cancer patients.

We and others reported that cell polarity proteins function as tumor suppressors in mammals. However, recent studies from our laboratory have challenged this notion by demonstrating that cell polarity proteins such as LLGL2, Pard6b, and Scribble function as positive regulators of cancer cell growth and therapy resistance by regulating cellular metabolism and trafficking of cell surface proteins. Consistent with our findings, many cell polarity proteins are overexpressed or amplified in cancer, highlighting a new opportunity for investigating how cell polarity proteins regulate changes in cellular metabolome, cell surface proteome, and signal transduction pathways to promote metastatic cancer progression and resistance to treatments, including immunotherapy.

Lastly, we have recently developed a method to co-culture tumor organoids with autologous peripheral blood-derived mononuclear cells. This method functions as an empirical platform for a dramatic (1000–100,000 fold) clonal expansion of cytotoxic T cells activated by antigens presented on the tumor cell surface. The organoid-primed cytotoxic T, opT, cells generated from co-culture create an opportunity to identify tumor-selective cytotoxic cells and the TCRs for use in immune-therapy applications for cancers including breast, pancreas, and head and neck.

Biography

Senthil K. Muthuswamy, Ph.D., received his Ph.D. from McMaster University, Canada, and did his postdoctoral fellowship with Joan Brugge at Harvard Medical School. He began his independent faculty position at Cold Spring Harbor Laboratory, New York, in 2001 and subsequently moved to Princess Margaret Cancer Centre, Toronto. In 2015 he joined the Department of Medicine and Cancer Center at Beth Israel Deaconess Medical Center, Harvard Medical School, where he served as the Director of the Cell Biology Program. Dr. Muthuswamy was among the first to employ three-dimensional cell culture (organoids) to bridge the gap between growing cells as a flat monolayer and tumors growing in vivo. Ongoing work in his laboratory uses organoids for investigating metastatic cancer progression, therapy resistance, biomarker discovery, T cell–tumor cell interactions, and personalization of treatment for cancer patients. In addition, research from his laboratory is defining how cell polarity proteins function as promoters of metastasis and therapy resistance by regulating cellular metabolome, cell surface proteome, and signaling pathways.

Dr. Muthuswamy is a recipient of the Rita Allen Scholar award, V Foundation Scholar award, US Army Era of Hope Scholar Award, Lee K. and Margaret Lau Chair in Breast Cancer Research, and the Canadian Society of Biochemistry and Molecular & Cellular Biology young scientist award for research achievements.

Related Scientific Focus Areas

This page was last updated on Friday, September 16, 2022