Center for Regenerative Medicine

photo

Ramaswamy Lab

Research topics include: Cancer Genetics and Genomics; Progression; Invasion and Metastasis; Drug and Treatment Resistance; Computational and Systems Biology.

Sridhar Ramaswamy, MD
Associate Professor of Medicine

Harvard Medical School

Tucker Gosnell Investigator
Attending Physician

Massachusetts General Hospital Cancer Center
Massachusetts General Hospital Center for Regenerative Medicine

Associate Member
Broad Institute of Harvard and MIT
Harvard Stem Cell Institute

Research Summary
Our laboratory is working to understand how human cancer genomes regulate solid tumor growth, metastasis, dormancy, and drug response. Our major goal is to use insights from our studies to develop entirely new strategies for the personalized diagnosis and treatment of cancer.

Research Projects

We are working to identify mechanisms that enable cancers to metastasize, but then lay dormant at distant sites, only to recur late after apparently curative treatment. Our initial work in cancer genomics suggested a paradigm-shifting model whereby cancer cells metastasize early (rather than late) during solid tumor evolution (Nature Genetics (2003)). We have subsequently combined molecular and cell biology, imaging, bioengineering, and systems approaches to identify pathways that regulate cancer cell metastasis and dormancy (PNAS (2010), PNAS (2011)). We are also using advanced genomics, computation, and statistical data-mining to: 1) identify diagnostic, prognostic, and drug response genes across a spectrum of cancer types (e.g. PNAS (2001), Nature (2012)); and 2) discover molecular pathways in cancer and stem cells that regulate proliferation, invasion, differentiation, and resistance to therapeutics (e.g. Cell (2003), Cell (2004), Cell (2010), Cell (2012), Science (2013)).

Asymmetric Cancer Cell Division

Over the last five years, we have developed a special interest in the molecular basis of asymmetric cancer cell division. We have found that rapidly proliferating cancer cells occasionally divide asymmetrically to produce slowly proliferating “G0-like” progeny that are highly treatment resistant both in vitro and in cancer
patients. We have developed reliable methods for the identification, isolation, tracking, and experimental study of these G0-like cells. Our molecular and cellular studies have revealed that partial suppression of the AKT/PKB signaling pathway (analogous to rheostatic control) induces an epigenomic network that regulates asymmetric cancer cell division and the production of G0-like cells. Since virtually all tumors depend on AKT signaling for their growth and survival, we believe that understanding the mechanisms underlying this quantitative regulation of AKT signaling and asymmetric cancer cell division in detail might enable us to develop entirely new strategies to diagnose and therapeutically target a wide variety of different cancer types where dormant cancer cells are difficult to eradicate. Current projects include 1) identifying upstream pathways that partially suppress AKT signaling in rare, asymmetrically dividing cancer cells; 2) defining precisely the epigenomic posture of G0-like progeny using next-generation sequencing approaches; 3) dynamically visualizing cancer cells undergoing asymmetric division with live- cell imaging approaches; and 4) asking how asymmetric cancer cell division contributes to tumor metastasis, dormancy, and treatment resistance in vivo and in patients.
Cancer Metastasis

We have a major interest in understanding how human cancer genomes regulate solid tumor progression. We are particularly interested in defining transcriptional networks that regulate metastasis, dormancy, and drug response. Several years ago, we and others found that multi-gene transcriptional signatures are expressed by a majority of malignant cells within tumors that are destined to metastasize. These studies spurred the development and deployment of widely-used gene signature-based clinical diagnostics for the diagnosis and risk-stratification of cancer patients with different tumor types. We recently found that virtually all of these “poor prognosis” signatures indirectly reflect the activity within tumors of the MYC transcription factor. Moreover, we found that MYC specifically regulates cancer cell invasion and metastasis (apart from it’s well studied roles in proliferation and survival), suggesting that quantitative increases in MYC activity may ultimately cause solid tumor metastasis. Since MYC is arguably the most common human oncogene, understanding precisely how MYC regulates metastasis might suggest new strategies for therapeutically targeting advanced cancers. Current projects include 1) DNA-seq, RNA-seq, and ChIP-seq profiling to comprehensively define the metastasis-related MYC transcriptional state; and 2) functional studies probing this MYC network in vitro and in vivo.

Center for Computational Discovery
A major challenge in modern cancer research is the generation, storage, analysis, and interpretation of complex experimental data. Individual experiments using cutting-edge technologies can generate terabytes of data that must be quantitatively mined to identify important cancer genes, pathways, and drug associations, to drive the discovery of new biomarkers and drug targets. Scientists in our Center for Computational Discovery (CCD) have significant expertise in the analysis of high-throughput biological data from across the current technological spectrum including next-generation sequencing (DNA, RNA, ChIP-seq), microarrays (e.g. SNP, CHG, Expression, Tiling, ChIP-Chip), proteomics (array-based), genome-scale RNAi and chemical screens, and high-throughput microscopy. CCD scientists are developing new methods for the analysis, display, and storage of large data sets generated with these cutting edge technologies. CCD scientists also work closely with a wide-spectrum of investigators throughout the Cancer Center on a variety of translational and fundamental research projects at any given time, both as collaborators and consultants. In approaching new projects, we apply established analytic tools and also develop, implement, and deploy customized tools depending on specific requirements. Current projects involve 1) cancer genome discovery in circulating tumor cells; 2) cancer cell line pharmacogenomics; 3) epigenomics; 4) data integration and meta-analysis; and 5) predictive modeling.

 

Research PositionsPostdoctoral Research Fellow 
Cancer Biology
A Postdoctoral Research Fellow position is available to study human solid tumor metastasis, drug resistance, and/or dormancy. The candidate must have recently received a PhD or MD PhD degree in the biological sciences, and be highly motivated and well versed in basic molecular biology, cell biology, and biochemical techniques with special interests in transcriptional regulation, epigenetics, stem cell biology, and/or live cell imaging. The Fellow will have simultaneous academic appointments at the Massachusetts General Hospital, Harvard Medical School, and the Broad Institute. The laboratory provides a rich intellectual environment within a group of highly collaborative investigators, with full integration into the large research communities of the Massachusetts General Hospital, Harvard University, the Broad Institute, and the Harvard Stem Cell Institute.

Interested candidates should e-mail a brief cover letter and CV to:
Sridhar Ramaswamy, MD
Massachusetts General Hospital Cancer Center/Harvard Medical School 
185 Cambridge Street, Boston, MA 02114

 

Staff Scientist 
Computational Biology & Bioinformatics

A Staff Scientist position is available for a highly qualified expert in Computational Biology and Bioinformatics in the Center for Computational Discovery at the Massachusetts General Hospital Cancer Center and Harvard Medical School. The individual will join a highly motivated, collaborative, and multi-disciplinary team using high-throughput approaches to answer applied and fundamental questions in cancer biology and medicine. He or she will provide bioinformatics and computational biology expertise for analyzing a significant next generation sequencing (NGS) data stream (e.g., DNA-seq, RNA-seq, ChIP-seq, methylation, etc.) and collaborate across the Mass General Cancer Center with different research groups on related projects. We seek a highly motivated and independent thinker with a PhD or MS in Mathematics, Statistics, Computer Science, or Bioinformatics/Computational Biology, significant familiarity with statistical computing and NGS tools, strong interpersonal skills, and a track record of collaborative work in a multidisciplinary research environment.

Interested candidates should e-mail a brief cover letter and CV to:
Sridhar Ramaswamy, MD OR Ben Wittner, PhD 
Center for Computational Discovery
Massachusetts General Hospital Cancer Center/Harvard Medical School 
185 Cambridge Street Boston, MA 02114

Stand Up To Cancer

Sridhar Ramaswamy, MD, awarded a Research Innovation Grant to fund his lab’s work on the mechanisms of cancer cell survival, metastasis, drug resistance, and dormancy.

Sridhar Ramaswamy, MD, awarded the Sidney Kimmel Foundation Award in Translational Research

The Kimmel Scholar Awards were created in 1997 to further the careers of gifted, young scientists involved in cancer research.

Ramaswamy awarded Howard Hughes Medical Institute Physician-Scientist Early Career Award

Each year, alumni of the HHMI-National Institutes of Health Research Scholars Program and the HHMI Research Training Fellowships for Medical Students are invited to apply for Early Career Awards as they begin their careers as physician-scientists.

Sridhar Ramaswamy, MD, elected to the American Society of Clinical Investigation (ASCI)

The ASCI is an honor society of physician-scientists, who translate findings in the laboratory to the advancement of clinical practice.

Big Data’s Powerful Promise

Mass General researchers believe computational biology will lead to more accurate diagnosis of a broad range of conditions and improved personalized treatments.

Metastasis: The Killing Fields

Cancer begins its spread much earlier than thought, hijacks healthy cells to help it proliferate, and activates a dormant embryonic program that gives it license to travel.

Recent Publications

Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff S, Ciciliano JC, Wells, MN, Shah AM, Concannon K, Sequist LV, Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 2013; 339:580-84. PMID: 23372014

Polo JM, Anderssen E, Walsh RM, Schwarz B, Borkent M, Apostolou E, Stadtfeld M, Figueroa ME, Robinton D, Natesan S, Melnick A, Ramaswamy S, Hochedlinger K. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 2012; 151:1617-1632. PMID: 23260147

Garnett MJ, Edelman EJ, Heidorn SJ, Greenman C, Dastur A, Lau KW, Greninger P, Thompson IR, Luo XN, Soares J, Liu Q, Iorio F, Milano RJ, Bignell G, Tam AT, Davies H, Stevenson JA, Barthorpe A, Lutz SR, McLaren-Douglas A, Mitropoulos X, Mironenko T, Thi H, Richardson L, Zhou W, Jewitt F, Zhang T, O’Brien P, Price S, Hur W, Yang W, Deng X, Butler A, Choi HG, Chang JW, Baselga J, Stamenkovich I, Engelman J, Sharma SV, Saez-Rodriguez J, Gray NS, Settleman J, Futreal PA, Haber DA, Stratton MR, Ramaswamy S, McDermott U, Benes C. A systematic screen identifies genomic biomarkers of drug sensitivity in cancer cells. Nature 2012; 483:570-577. PMID: 22460902

Dey-Guha I, Wolfer A, Yeh AC, Albeck JG, Darp R, Leon E, Wulfkuhle J, Petricoin EF, Wittner BS, Ramaswamy S. Asymmetric cancer cell division regulated by AKT. Proc Natl Acad Sci USA 2011; 108:12845-12850. PMID: 21757645

Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, McDermott U, Azizian N, Zou L, Fischbach MA, Wong KK, Brandstetter K, Wittner B, Ramaswamy S, Classon M, Settleman J. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141:69-80. PMID: 20371346

Wolfer A, Wittner BS, Irimia D, Flavin RJ, Lupien M, Gunawardane RN, Meyer CA, Lightcap E, Tamayo P, Mesirov JP, Liu XS, Shioda T, Toner M, Loda M, Brown M, Brugge JS, Ramaswamy S. MYC regulation of a poor prognosis metastatic cancer cell state. Proc Natl Acad Sci USA 2010; 107:3608-3703. PMID: 20133671

Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nature Genetics 2003; 33:49-54. PMID: 12469122

Ramaswamy S, Tamayo P, Rifkin R, Mukherjee S, Yeang CH, Angelo M, Ladd C, Reich M, Latulippe E, Mesirov JP, Poggio T, Gerald W, Loda M, Lander ES, Golub TR.  Multi-class cancer diagnosis using tumor gene expression signatures. Proc Natl Acad Sci USA 2001; 98:15149-15154. PMID: 11742071

View a list of additional publications by researchers at the Ramaswamy Laboratory

 

Ramaswamy Laboratory

Richard B. Simches Research Center
185 Cambridge Street
CPZN 4200
Boston, MA 02114

Phone: 617-643-3140
Fax: 617-643-3170
Email: sridhar@mgh.harvard.edu


Directions to the Ramaswamy Lab.