ScriKD Laminin5-Modified-HW.jpg
 

Organoids, Cell Polarity, Immunology & Translational Research

 

Dr. Senthil K Muthuswamy

muthuswamys.jpg

Principal Investigator

Director, Cell Biology Program, Cancer Center, Co-Chief Division of Translational Research and Technology Innovation, Associate Professor Departments of Medicine and Pathology Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA

Contact :

Email : smuthusw@bidmc.harvard.edu

Lab Address : 3 Blackfan circle, CLS 417D, Boston, MA 02115

Phone : 617-735-2238

After my early training in plant genetics, I moved into the field of cancer research for my graduate studies. Being a newcomer to the field, I first chose to develop a basic understanding of the disease and enrolled myself in pathology of cancer courses offered to medical students. What I learned in the course opened my eyes and my mind to the importance of cell and tissue morphology in diagnosing and understanding disease states. I also realized that to understand the biology of a disease, one needs to use models that resemble the disease, which laid the foundation for what we do in my laboratory today. We develop three-dimensional culture methods to grow normal, or tumor cells as organoids with a specific goal of recreating the morphology of normal and disease states to the best possible extent. We use these normal or tumor epithelial organoid models to understand cell biological mechanisms of normal development and disease progression; to study interaction with immune cells; to identify new therapies and; to assist oncologists in personalizing treatment decisions for cancer patients.

I believe that being a scientist is not just a profession; it is a passion. A passion worth pursuing for it is the only path to discover the unknown and to help people suffering from incurable diseases such as cancers. In addition, I take pride in being a citizen of science and help train the next generation of scientists discover their passion for scientific pursuit and sharpen their analytical and problem solving skills. Outside of science, I enjoy photography, gardening, hiking, and playing badminton.

RESEARCH

Organoids

Over the past 20 years, our laboratory has made significant contributions to the development of three-dimensional culture and organoid (mini-organ) models. In 2001, I developed a 3D culture method for growing MCF-10A cells and demonstrated the use of the platform for modeling transformation induced by the ErbB family of receptors (Nat. Cell Biol. 2001).We subsequently reported on the ways to use the models to understand morphogenesis, oncogene-induced effects on cell polarity, and transformation. More recently, we have expanded the utility of the 3D culture method to growing human pancreatic exocrine cells as ductal and acinar organoids (Nat. Med, 2015). We continue to develop new organoid models for other organ sites and continue to use these patient-derived organoid models from breast and pancreatic cancer for translational and clinical research. Active studies include identification of new drug-sensitivities, modeling drug resistance, biomarker discovery, and clinical trials evaluating use of co-clinical organoid pipeline to personalize treatment choices. On a broader note, it is worth noting that the use of 3D culture methods in cancer research has gone from being a rarity in 2001 to becoming the norm today. 

Cell Polarity

Rethinking the role of cell polarity proteins in cancer:  Studies in Drosophila models and mammals, including ours (Cell, 2008), have defined cell polarity proteins as tumor suppressors. However, recent studies from our laboratory demonstrate that many cell polarity proteins function as promoters of cell proliferation in cancer. We discovered that Par6 is overexpressed in breast cancer and promotes cell proliferation by activating MAPK signaling (Can. Res., 2008). Transgenic mouse models of a mislocalized mutant of Scribble develop mammary tumors by activating S6 kinase (Can Res, 2014). More recently, we demonstrated that LLGL2 is overexpressed in ER+ breast cancer cells. In this context, LLGL2 promotes adaptation to nutrition stress and tamoxifen resistance by increasing the cell surface level of the leucine transporter, SLC7A5, identify a role for cell polarity proteins as drivers of drug resistance (Nature, 2019). Thus, findings our laboratory is challenging the dogma that cell polarity proteins function as tumor suppressors and beginning to identify them as tumor promoters. Moving forward, we aim to understand why many cell polarity proteins are over expressed or amplified in various cancers to determine if cell polarity proteins are a hitherto unappreciated class of drug targets and biomarkers.

Cell polarity and metastasis:Studies from our laboratory showed that activation of ErbB2 induces disruption of apical-basal polarity by deregulating the Pa6/aPKC/Pard3 complex and tight junctions(Nat. Cell Biol. 2006). Consistent with a tumor-suppressive role for some polarity proteins, we showed that the downregulation of Pard3 cooperates with ErbB2 to induce cell invasion and lung metastasis in the absence of an overt EMT phenotype(Nat. Cell Biol. 2013). Our findings provide new insights to suggest that subtle changes in epithelial cell behavior, such as decreased cell-cell cohesion, are sufficient to confer metastatic behavior to tumor epithelia. To study metastasis and epithelial differentiation state plasticity in culture and in vivo, we recently reported the developed of new reporter system that can mark and eliminate basal or luminal epithelial cells(PLOS Bio, 2018). We continue to investigate mechanisms of metastasis with the intent of finding ways to intervene.

Immunology

Cell polarity and immune cells:  Apart from epithelial cells, we have identified an unexpected role for the cell polarity protein Scribble in macrophages. We discovered that Scrib polarizes to phagosomes and regulates the generation of reactive oxygen species to kill bacteria and control M1 versus M2 macrophage polarization and inflammation (Nat. Cell Biol. 2016). This finding has now opened new doors for investigating the role of cell polarity proteins in immune cells.

Immune-Tumor cells interaction: We are developing new methods for using organoids to model the interaction between tumor cells and T cell to understand the mechanisms of immune regulation in cancer and to discover new therapeutic approaches.

TEAM

Instructors in Medicine

Untitled-1.jpg

LING HUANG, PH.D

Instructor in Medicine

Research Topic : Continue advancing our stem cell-derived and tumor organoid method for human pancreatic cancer and use them to model human pancreatic cancer initiation in culture

lhuang6@bidmc.harvard.edu

Bruno Bockorny.jpeg

BRUNO BOCkorny, MD

Instructor in Medicine; GI Oncology attending

Research Topic: My research is primarily focused on developing new approaches to discover biomarkers to diagnose pancreatic cancer and monitor disease state while patients are on treatment.

Hobbies: avid soccer player and fan

bbockorn@bidmc.harvard.edu

joe12.jpg

Joe grossman, MD

Instructor in Medicine; GI Oncology attending

Research Topic :Principal investigator of the Dana Farber Harvard Cancer Center protocol “ A Feasibility Trial of Patient Derived Organoids as a Biomarker for Response to Therapy in Pancreatic Cancer” – the HOPE trial (Harnessing Organoids for PErsonalized Therapy)

Hobbies: Family, playing music, cooking.

jgrossm2@bidmc.harvard.edu

 

Postdocs

Sofia Perea Del Pino, Ph.D

Instructor in Medicine, Clinical research Staff Scientist II

Research Topic : HOPE clinical trial

sperea@bidmc.harvard.edu

IMG_2771.jpg

Qingda Meng, PH.D

Research fellow

Research Topic: immunotherapy for pancreatic cancer

Hobbies: wood, stone and fossil collection

qmeng@bidmc.harvard.edu

Shanshan%2520Xie_photo.jpg

Shanshan Xie, Ph.D

Research fellow

Research Topic:Immunotherapy for breast cancer

Hobbies: Traveling, Hiking and Bicycling.

sxie@bidmc.harvard.edu

Oliphant%20Headshot.jpeg


Mike oliphant, Ph.D

Research fellow
Research Topic: ER+ Breast Cancer, Drug Resistance

Hobbies: Hanging out with my son (Lincoln), Chicago Sports, pick up basketball and craft beer!

michael_oliphant@hms.harvard.edu

Desai_140618_02.jpg

Ridhdhi Desai, Ph.D

Research fellow

Research Topic : Modeling early stage human pancreatic lesions

Hobbies : Travelling and Enjoying Outdoors, Cooking, Spending time with family, board games and Hockey.

rrdesai@bidmc.harvard.edu

c19c92ef-5a67-4599-be78-caa59d2592ed.jpg

Arindam Bose, Ph.D

Research fellow

Research Topic : My goals are to overcome chemoresistance to DNA damaging agents (DDA) in pancreatic ductal adenocarcinoma (PDAC) by identifying DNA damage repair (DDR) and tolerance pathways used by PDAC epithelial cells.
Hobbies : Travel Planning, Cooking, Music and Soccer.

abose@bidmc.harvard.edu

IMG_3283.jpg

Weilin LI, PH.D

Research fellow

Research Topic : Immunotherapy for Pancreatic Cancer

Hobbies : Billiards, Travel, Music

wli9@bidmc.harvard.edu

Research Associates/ Staff scientist

IMG_1215.jpg

Dipikaa Akshinthala, MSc, MS

Senior Research Associate

Research Topic: Generate and Characterize patient derived organoid models for Breast and pancreas cancers

Hobbies: Cooking, avid reader, music, traveling and hiking

sakshint@bidmc.harvard.edu

Shibani Mukherjee, Ph.D

Staff Scientist I

Research Topic : Glioblastoma organoids

smukher3@bidmc.harvard.edu

Research Assistants

lukas.jpg

 Lukas Ritzer, BS

Research Assistant

Research Topic: Investigating the role of cell polarity proteins in breast cancer proliferation.

Hobbies: I enjoy wilderness camping, raising honeybees, and other outdoor activities. I also have interests in martial arts, soccer, and chess. 

lritzer@bidmc.harvard.edu

Screenshot_20190826-104951_Gallery.jpg

Matt Digby, MS

Clinical Research assistant

Research Topic : preclinical studies

mdigby1@bidmc.harvard.edu

Students

photo.jpg

Christine M Lim

Visiting student- Candidate for BS Bioengineering, From Nanyang Technological University, 2021

Research Topic : Genetic mutations in pancreatitis. Computational predictive models for drug response in pancreatic cancer.

Hobbies : Trekking, Swimming, Dancing and Chinese Orchestra

 Lab News & Events

Our recent discovery on an unexpected role for the cell polarity protein, LLGL2, regulating intracellular leucine levels in breast cancer and this biology regulating endocrine therapy resistance has received significant media attention.

Science Daily: https://www.sciencedaily.com/releases/2019/04/190417132750.htm

Harvard Gazzette: https://news.harvard.edu/gazette/story/2019/05/dietary-link-found-to-drug-resistant-breast-cancer/

MedicalNewsToday: https://www.medicalnewstoday.com/articles/325007.php

Independent: https://www.independent.co.uk/news/health/breast-cancer-vegetarian-diet-chemotherapy-animal-protein-leucine-a8874351.html

GEN news: https://www.genengnews.com/news/breast-cancer-drug-resistance-linked-to-diet-high-in-leucine/

BioMed Advances: https://biomedadvances.com/er-positive-breast-cancer-cell-proliferation-resistance-tamoxifen-linked-to-high-leucine-levels/

Mammary Cell News: https://www.mammarycellnews.com/issue/volume-11-14-apr-18/

LEA Foundation: https://www.leafscience.org/aggregator/diet-high-in-leucine-may-fuel-breast-cancer039s-drug-resistance/

MSN news: https://www.msn.com/en-my/health/medical/low-protein-diet-could-prevent-breast-cancer-cells-resisting-treatment-study-suggests/ar-BBW35fT

NewHopeUnlimited: https://www.newhopemedicalcenter.com/blogs/study-high-leucine-diets-may-thwart-breast-cancer-therapy/

Media related to our organoid efforts:

 BIDMC: https://www.bidmc.org/give/giving-matters/past-stories/breaking-the-silence/organoids

NCI: https://www.cancer.gov/research/key-initiatives/ras/ras-central/blog/2016/senthil-uthuswamy-interview

Science Daily: https://www.sciencedaily.com/releases/2015/10/151027154933.htm

EurekAlert: https://www.eurekalert.org/pub_releases/2015-10/bidm-3pc102715.php

Annual Lab Hiking trip- Halibut state park, MA- July 2019

 

Bye Bye Yasu !! Good Luck for your faculty position in Japan.

yasu.jpg
 

Annual Lab retreat - Topsham, Vermont -Oct 2018

 

Lab dressed in Purple in honor of World Pancreatic cancer Day.

SKM_4085.JPG
 

Holiday Bowling !

IMG_0155.jpeg
 

Pancreatic Cancer walk- Boston

IMG_9921.jpeg

 Publications

Publications (last three years)

  1. Saito Y, Li L, Coyaud E, Luna A, Sander C, Raught B, Asara J, Brown M, and Muthuswamy SK. (2019) 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.

  2. Natividad RJ, Lalli ML, Muthuswamy SK, Asthagiri AR. (2018) Golgi Stabilization, Not Its Front-Rear Bias, Is Associated with EMT-Enhanced Fibrillar Migration. Biophys J. 2018 Nov 20;115(10):2067-2077. doi: 10.1016/j.bpj.2018.10.006. PMID: 30366626

  3. 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 K, Hannon GJ, Muthuswamy SK (2018) Reporters to mark and eliminate basal or luminal epithelial cells in culture and in vivo. PLOS Biology, 16(6):e2004049. doi: 10.1371/journal.pbio.2004049. PMID:299248084

  4. Muthuswamy SK. (2018) Organoid Models of Cancer Explode with Possibilities. Cell Stem Cell. 2018 Mar 1;22(3):290-291. doi: 10.1016/j.stem.2018.02.010. PMID: 29499146

  5. Götz M, Muthuswamy SK. (2018) Editorial overview: Cell differentiation and development: New kids in the block-new tools and concepts opening new doors in development. Curr Opin Cell Biol. 2017 Dec;49:iv-v. doi: 10.1016/j.ceb.2018.01.012. PMID: 29463399

  6. Saito Y, Desai RR, Muthuswamy SK. (2018) Reinterpreting polarity and cancer: The changing landscape from tumor suppression to tumor promotion. Biochim Biophys Acta. 1869(2):103-116. doi: 10.1016/j.bbcan.2017.12.001. PMID: 29369778

  7. Gilles ME, Hao L, Huang L, Rupaimoole R, Lopez-Casas PP, Pulver E, Jeong JC, Muthuswamy SK, Hidalgo M, Bhatia SN, Slack FJ. (2018) Personalized RNA-medicine for pancreatic cancer. Clin Cancer Res. Apr 1; 24(7):1734-1747. doi: 10.1158/1078-0432.CCR-17-2733. PMID: 29330203

  8. Dai X, Gan W, Li X, Wang S, Zhang W, Huang L, Liu S, Zhong Q, Guo J, Zhang J, Chen T, Shimizu K, Beca F, Blattner M, Vasudevan D, Buckley DL, Qi J, Buser L, Liu P, Inuzuka H, Beck AH, Wang L, Wild PJ, Garraway LA, Rubin MA, Barbieri CE, Wong KK, Muthuswamy SK, Huang J, Chen Y, Bradner JE, Wei W. (2017) Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat Med. Sep; 23(9):1063-1071. doi: 10.1038/nm.4378. PMID: 28805820

  9. Muthuswamy, SK. (2017) Bringing together the organoid field: from early beginnings to the road ahead. Development Mar, 144 (6): 963-967. doi: 10.1242/dev.144444. PMID: 28292842

  10. Zheng, W., Umitsu, M., Jagan, I., Tran, CW., Ishiyama, N., BeGora, M., Araki, K., Ohashi, PS., Ikura, M., and Muthuswamy, SK. (2016) An interaction between Scribble and the NADPH oxidase complex controls M1 macrophage polarization and function. Nat. Cell Biol. Nov; 18 (11): 1244 - 52. doi: 10.1038/ncb3413. PMID:27694890

  11. Milano, DF., Natividad, R., Saito, Y., Luo, CY., Muthuswamy, SK., and Asthagiri, AR. (2016) Positive quantitate relationship between EMT and contact-initiated sliding on fiber-like tracks. Biophys J. Oct 4; 111 (7): 1569 – 74. doi: 10.1016/j.bpj.2016.08.037. PMID:27705778

  12. Milano DF, Ngai NA, Muthuswamy SK, Asthagiri AR. (2016) Regulators of Metastasis Modulate the Migratory Response to Cell Contact under Spatial Confinement. Biophys J. Apr 26;110 (8):1886-95. doi: 10.1016/j.bpj.2016.02.040. PMID:27119647

  13. Baker, L, BeGora, M, Yeung FA, Feigin, ME, Rosenberg, AZ, Lowe, SW, Kislinger, T, and Muthuswamy, SK. (2016) SCRIBBLE is required for pregnancy-induced alveologenesis in the adult mammary gland. J. Cell Sci. 129 (12): 2307 - 15. doi: 10.1242/jcs.185413. PMID:27179074

For a full list of publications: https://www.ncbi.nlm.nih.gov/pubmed/?term=muthuswamy+sk

Alumni

Graduate Students:

  1. Marissa Nolan , Ph.D. from 2002-2008

  2. Alexandra Lucs, Ph.D. from 2002-2007

  3. Min Yu, Ph.D. from 2003-2006

  4. Avi Rosenberg, MD,Ph D. from 2003-2008

  5. Isabela Sujka, MSc. From 2004-2006

  6. Bin Xue, Ph.D. from 2007-2012

  7. Leena Baker, Ph.D. from 2010-2016

  8. Laurie Siefried, Ph.D. from 2011-2019

    Postdoctoral fellows:

  1. Bin Xiang, Ph.D. from 2002-2006

  2. Lixing Zhan, Ph.D. from 2004-2008

  3. Victoria Aranda, Ph.D. from 2004-2008

  4. Samit Chatterjee, Ph.D. from 2006-2010

  5. Michael Feigin, Ph.D. from 2008-2013

  6. Weiyue Zheng, Ph.D. from 2008-2015

  7. Kannan Krishnamurthy, Ph.D from 2009-2011

  8. Elaine McSherry, Ph.D from 2010-2012

  9. Hui Wang, Ph.D. from 2013-2015

  10. Ishaan Jagan, Ph.D from 2011-2016

  11. Olmo Sonzogni, Ph.D from 2013-2016

  12. Ann-Marie Fortier, Ph.D from 2013-2017

  13. Yasu Saito, Ph.D from 2014-2019

    Clinical Fellows

  1. Catherine O’Brien, MD from 2011-2012

  2. Courtney Burrows, M.D from 2015-2017

  3. Omar Gandarilla, MD from 2017-2019

    Summer fellows, visiting scholars, Undergrads

  1. Winfred Fraizer – 2002

  2. John McIntyre --2003

  3. Srinjan Basu - 2004

  4. Joe Calarco - 2005

  5. Zandra Walton - 2008

  6. Dr. Jonathan Chernoff

  7. Agata Tinnirello -2010

  8. Maria Chiara - 2018

  9. Avni Bhagat 2018

  10. Iyani Kelly 2018

  11. Elizabeth Ferrer 2019

  12. Alejandro Gonzalez, 2019

    Lab/Research Assistants/Associates

  1. Teresa Haire

  2. Ken Bergami

  3. Kiyomi Araki

  4. Muluken Belew

  5. Kai Huang

  6. Karthika Yoganathan

  7. Michael Begora

  8. Faith Yeung

  9. Nicholas Ngai

  10. Jun Ikura

AFFILIATIONS & Funding sources

Slide1.jpeg