Muthuswamy Lab
Senthil Muthuswamy, Ph.D.
Research
The Muthuswamy laboratory was among the first to employ three-dimensional cell culture (now referred to as organoid culture) to bridge the gap between growing cells as a flat monolayer and tumors growing in vivo. They apply a microscope-to-stethoscope approach that combines basic cell biology investigations with clinical translation, as evidenced by the successful completion of a clinical trial: Harnessing Organoids for PErsonalized therapy (HOPE) in pancreatic cancer. Studies in his lab use the organoid platform to understand how cell polarity proteins regulate drug resistance and cell metabolism, T-cell-tumor cell interactions, and metastatic progression and to develop personalized cancer treatments.
Ongoing studies address challenging, and provocative questions in cancer cell biology using tumor organoid or mouse models, T-cell co-culture, genetic screens, cell surface proteomics, single-cell analysis, metabolomics, and high-resolution imaging approaches.
Team
Publications
Publications (last three years)
Orr S, Huang L, Moser J, Stroopinsky D, Gandarilla O, DeCicco C, Liegel J, Tacettin C, Ephraim A, Cheloni G, Torres D, Kufe D, Rosenblatt J, Hidalgo M, Muthuswamy SK, Avigan D. Personalized tumor vaccine for pancreatic cancer. Cancer Immunol Immunother. 2022 Jul 14. doi: 10.1007/s00262-022-03237-x. PMID: 35834008
Saito Y, Matsuda S, Ohnishi N, Endo K, Ashitani S, Ohishi M, Ueno A, Tomita M, Ueda K, Soga T, Muthuswamy SK. Polarity protein SCRIB interacts with SLC3A2 to regulate proliferation and tamoxifen resistance in ER+ breast cancer. Commun Biol. 2022 May 2;5(1):403. doi: 10.1038/s42003-022-03363-3. PMID: 35501367
Gil Del Alcazar CR, Trinh A, Alečković M, Rojas Jimenez E, Harper NW, Oliphant MUJ, 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 Jun 3;10(6):680-697. doi: 10.1158/2326-6066.CIR-21-0804. PMID: 35446942
Kahraman S, Dirice E, Basile G, Diegisser D, Alam J, Johansson BB, Gupta MK, Hu J, Huang L, Soh CL, Huangfu D, Muthuswamy SK, Raeder H, Molven A, Kulkarni RN. Abnormal exocrine-endocrine cell cross-talk promotes β-cell dysfunction and loss in MODY8. Nat Metab. 2022 Jan;4(1):76-89. doi: 10.1038/s42255-021-00516-2. PMID: 35058633
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 Nov;9(11):e003213. doi: 10.1136/jitc-2021-003213. PMID: 34789550
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. 2022 Feb 15;28(4):708-718. doi: 10.1158/1078-0432.CCR-20-4116. PMID: 34789479
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 Aug 27;7(35):eabj0364. doi: 10.1126/sciadv.abj0364. PMID: 34452919
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 Sep 2;184(18):4753-4771.e27. doi: 10.1016/j.cell.2021.07.020. PMID: 34388391
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 Jun 3;28(6):1090-1104.e6. doi: 10.1016/j.stem.2021.03.022. PMID: 33915081
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 CoQ10 induce ROS-mediated apoptosis in pancreatic cancer. Sci Rep. 2021 Mar 11;11(1):5749. doi: 10.1038/s41598-021-84852-z. PMID: 33707480
Muthuswamy SK. Self-organization in cancer: Implications for histopathology, cancer cell biology, and metastasis. Cancer Cell. 2021 Apr 12;39(4):443-446. doi: 10.1016/j.ccell.2021.01.010. PMID: 33513348
Huang L, Bockorny B, Paul I, Akshinthala D, Frappart PO, Gandarilla O, Bose A, Sanchez-Gonzalez V, Rouse EE, Lehoux SD, Pandell N, Lim CM, Clohessy JG, Grossman J, Gonzalez R, Del Pino SP, Daaboul G, Sawhney MS, Freedman SD, Kleger A, Cummings RD, Emili A, Muthuswamy LB, Hidalgo M, Muthuswamy SK. PDX-derived organoids model in vivo drug response and secrete biomarkers. JCI Insight. 2020 Nov 5;5(21):e135544. doi: 10.1172/jci.insight.135544. PMID: 32990680
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 Aug;19(8):1751-1760. doi: 10.1158/1535-7163.MCT-19-1166. PMID: 32499301
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 Nov 26;29(9):2672-2688.e7. doi: 10.1016/j.celrep.2019.10.110. PMID: 31775037
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 May;569(7755):275-279. doi: 10.1038/s41586-019-1126-2. PMID: 30996345
For a full list of publications: https://www.ncbi.nlm.nih.gov/pubmed/?term=muthuswamy+sk
News
Media Related to Our Organoid Efforts:
Structural Approach to Cancer
Harvard Medical School, May 4, 2021
Scientists create first-of-its-kind 3D organoid model of the human pancreas. Read more
New 3D organoid model of pancreas developed from human stem cells
Drug Target Review, April 29, 2021
Researchers have developed the first 3D organoid models of the pancreas that includes both the acinar and ductal structures. Read more
Researchers develop first 3D organoid models of the pancreas from human stem cells
Medical & Life Sciences News, April 28, 2021
Researchers at the Cancer Research Institute at Beth Israel Deaconess Medical Center (BIDMC) have successfully created the first three-dimensional (3D) organoid models of the pancreas from human stem cells. Unlike previous platforms for the study of pancreatic cancer, this first-of-its-kind organoid model includes both the acinar and ductal structures that play a critical role in the majority of pancreatic cancers. Read more
Scientists create first-of-its-kind 3D organoid model of the human pancreas
Medical Xpress, April 21, 2021
This year, more than 60,000 adults in the United States will be diagnosed with pancreatic cancer and, statistically, as few as 10 percent will survive five years after diagnosis, according to the American Cancer Society. Because pancreatic cancer is hidden deep within the body and often symptomless, it's frequently diagnosed after the disease has progressed too far for surgical intervention and/or has spread throughout the body. Read more
Lab Life
Annual Lab Hiking Trip - Halibut State Park, MA - July 2019
Bye Bye Yasu!! Good Luck for your faculty position in Japan.
Annual Lab Retreat - Topsham, Vermont - October 2018
Lab dressed in purple in honor of World Pancreatic Cancer Day.
Holiday Bowling!
Pancreatic Cancer Walk - Boston
Alumni
This is just a small sample of our alumni. Over the years, our laboratory has trained many outstanding postdoctoral, doctoral and undergraduate fellows.