Photo of Senthil K Muthuswamy,  PhD

Senthil K Muthuswamy, PhD

Beth Israel Deaconess Medical Center

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

Senthil K Muthuswamy, PhD

Beth Israel Deaconess Medical Center


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


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 Our unpublished studies have identified an unexpected role for SCRIB in macrophages, where SCRIB polarizes to phagosomes and regulates generation of reactive oxygen species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 from Harvard Catalyst Profiles

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  • Gil Del Alcazar CR, Trinh A, Aleckovic M, Rojas Jimenez E, Harper NW, Oliphant MU, Xie S, Krop ED, Lulseged B, Murphy KC, Keenan TE, Van Allen EM, Tolaney SM, Freeman GJ, Dillon DA, Muthuswamy SK, Polyak K. Insights into immune escape during tumor evolution and response to immunotherapy using a rat model of breast cancer. Cancer Immunol Res 2022. PubMed
  • Grossman JE, Muthuswamy L, Huang L, Akshinthala D, Perea S, Gonzalez RS, Tsai LL, Cohen J, Bockorny B, Bullock AJ, Schlechter B, Peters MLB, Conahan C, Narasimhan S, Lim C, Davis RB, Besaw R, Sawhney MS, Pleskow D, Berzin TM, Smith M, Kent TS, Callery M, Muthuswamy SK, Hidalgo M. Organoid Sensitivity Correlates with Therapeutic Response in Patients with Pancreatic Cancer. Clin Cancer Res 2021. PubMed
  • Meng Q, Xie S, Gray GK, Dezfulian MH, Li W, Huang L, Akshinthala D, Ferrer E, Conahan C, Perea Del Pino S, Grossman J, Elledge SJ, Hidalgo M, Muthuswamy SK. Empirical identification and validation of tumor-targeting T cell receptors from circulation using autologous pancreatic tumor organoids. J Immunother Cancer 2021. PubMed
  • Koikawa K, Kibe S, Suizu F, Sekino N, Kim N, Manz TD, Pinch BJ, Akshinthala D, Verma A, Gaglia G, Nezu Y, Ke S, Qiu C, Ohuchida K, Oda Y, Lee TH, Wegiel B, Clohessy JG, London N, Santagata S, Wulf GM, Hidalgo M, Muthuswamy SK, Nakamura M, Gray NS, Zhou XZ, Lu KP. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. Cell 2021. PubMed
  • Chafe SC, Vizeacoumar FS, Venkateswaran G, Nemirovsky O, Awrey S, Brown WS, McDonald PC, Carta F, Metcalfe A, Karasinska JM, Huang L, Muthuswamy SK, Schaeffer DF, Renouf DJ, Supuran CT, Vizeacoumar FJ, Dedhar S. Genome-wide synthetic lethal screen unveils novel CAIX-NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors. Sci Adv 2021. PubMed
  • Huang L, Desai R, Conrad DN, Leite NC, Akshinthala D, Lim CM, Gonzalez R, Muthuswamy LB, Gartner Z, Muthuswamy SK. Commitment and oncogene-induced plasticity of human stem cell-derived pancreatic acinar and ductal organoids. Cell Stem Cell 2021. PubMed
  • Dadali T, Diers AR, Kazerounian S, Muthuswamy SK, Awate P, Ng R, Mogre S, Spencer C, Krumova K, Rockwell HE, McDaniel J, Chen EY, Gao F, Diedrich KT, Vemulapalli V, Rodrigues LO, Akmaev VR, Thapa K, Hidalgo M, Bose A, Vishnudas VK, Moser AJ, Granger E, Kiebish MA, Gesta S, Narain NR, Sarangarajan R. Elevated levels of mitochondrial CoQ induce ROS-mediated apoptosis in pancreatic cancer. Sci Rep 2021; 11:5749. PubMed
  • Muthuswamy SK. Self-organization in cancer: implications for histopathology, cancer cell biology, and metastasis. Cancer Cell 2021. PubMed
  • Huang L, Bockorny B, Paul I, Akshinthala D, Frappart PO, Gandarilla O, Bose A, Sanchez-Gonzalez V, Rouse E, Lehoux S, Pandell N, Lim C, Clohessy JG, Grossman JE, Gonzalez RS, Perea S, Daaboul G, Sawhney M, Freedman SD, Kleger A, Cummings RD, Emili A, Muthuswamy L, Hidalgo M, Muthuswamy S. PDX-derived organoids model in vivo drug response and secrete biomarkers. JCI Insight 2020. PubMed
  • Ferguson FM, Liu Y, Harshbarger W, Huang L, Wang J, Deng X, Capuzzi SJ, Muratov EN, Tropsha A, Muthuswamy S, Westover KD, Gray NS. Synthesis and structure activity relationships of DCLK1 kinase inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold. J Med Chem 2020. PubMed
  • Dimitrov-Markov S, Perales-Patón J, Bockorny B, Dopazo A, Muñoz M, Baños N, Bonilla V, Menendez C, Duran Y, Huang L, Perea S, Muthuswamy SK, Al-Shahrour F, Lopez-Casas PP, Hidalgo M. Discovery of new targets to control metastasis in pancreatic cancer by single cell transcriptomics analysis of circulating tumor cells. Mol Cancer Ther 2020. PubMed
  • Ferguson FM, Nabet B, Raghavan S, Liu Y, Leggett AL, Kuljanin M, Kalekar RL, Yang A, He S, Wang J, Ng RWS, Sulahian R, Li L, Poulin EJ, Huang L, Koren J, Dieguez-Martinez N, Espinosa S, Zeng Z, Corona CR, Vasta JD, Ohi R, Sim T, Kim ND, Harshbarger W, Lizcano JM, Robers MB, Muthaswamy S, Lin CY, Look AT, Haigis KM, Mancias JD, Wolpin BM, Aguirre AJ, Hahn WC, Westover KD, Gray NS. Discovery of a selective inhibitor of doublecortin like kinase 1. Nat Chem Biol 2020; 16:635-643. PubMed
  • Park S, Brugiolo M, Akerman M, Das S, Urbanski L, Geier A, Kesarwani AK, Fan M, Leclair N, Lin KT, Hu L, Hua I, George J, Muthuswamy SK, Krainer AR, Anczuków O. Differential Functions of Splicing Factors in Mammary Transformation and Breast Cancer Metastasis. Cell Rep 2019; 29:2672-2688.e7. PubMed
  • Saito Y, Li L, Coyaud E, Luna A, Sander C, Raught B, Asara JM, Brown M, Muthuswamy SK. LLGL2 rescues nutrient stress by promoting leucine uptake in ER breast cancer. Nature 2019; 569:275-279. PubMed
  • Sonzogni O, Haynes J, Seifried LA, Kamel YM, Huang K, BeGora MD, Yeung FA, Robert-Tissot C, Heng YJ, Yuan X, Wulf GM, Kron KJ, Wagenblast E, Lupien M, Kislinger T, Hannon GJ, Muthuswamy SK. Reporters to mark and eliminate basal or luminal epithelial cells in culture and in vivo. PLoS Biol. 2018; 16:e2004049. PubMed
  • Gilles ME, Hao L, Huang L, Rupaimoole R, Lopez-Casas PP, Pulver E, Jeong JC, Muthuswamy SK, Hidalgo M, Bhatia SN, Slack FJ. Personalized RNA Medicine for Pancreatic Cancer. Clin Cancer Res 2018; 24:1734-1747. PubMed
  • Muthuswamy SK. Organoid Models of Cancer Explode with Possibilities. Cell Stem Cell 2018; 22:290-291. PubMed
  • Saito Y, Desai RR, Muthuswamy SK. Reinterpreting polarity and cancer: The changing landscape from tumor suppression to tumor promotion. Biochim Biophys Acta 2018; 1869:103-116. PubMed
  • Muthuswamy SK. Bringing together the organoid field: from early beginnings to the road ahead. Development 2017; 144:963-967. PubMed
  • Xue, B, Krishnamurthy, K, Allred, CA, Muthuswamy, SK. Loss of Par3 promotes breast cancer metastasis by compromising cell-cell cohesion. Nat Cell Biol ; 15:189-200.
  • 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 ; 135:865-78.
  • 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 ; 8:1235-45.
  • 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 ; 21:1364-71.