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Tucker Gosnell Center for Gastrointestinal Cancers
Sridhar Ramaswamy, MDAssociate Professor of MedicineHarvard Medical School
Attending PhysicianTucker Gosnell InvestigatorSamana Cay MGH Research ScholarMassachusetts General Hospital Cancer Center
Associate MemberBroad Institute of Harvard and MITHarvard Stem Cell InstituteHarvard-Ludwig Center for Cancer Research
The Ramaswamy laboratory is working to understand how solid tumor metastasis, dormancy, and drug resistance interrelate. Our major goal is to use insight from our studies to devise new strategies for the combination targeting of advanced cancers. Our multidisciplinary approach integrates clinical studies in solid tumor patients with experimental approaches in cancer, computational, & systems biology.
Sridhar Ramaswamy, MDPrincipal Investigator
Ramaswamy Lab Photo Gallery
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)).
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.
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.
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 Cancer Systems Discovery (CCSD) 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. CCSD scientists are developing new methods for the analysis, display, and storage of large data sets generated with these cutting edge technologies. CCSD 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.
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, MDMassachusetts General Hospital Cancer Center/Harvard Medical School
185 Cambridge Street, Boston, MA 02114
A Postdoctoral Research Fellow and/or 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
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
Interested candidates should e-mail a brief cover letter and CV to:
Sridhar Ramaswamy, MD OR
Ben Wittner, PhDCenter for Computational DiscoveryMassachusetts General Hospital Cancer Center/Harvard Medical School 185 Cambridge Street Boston, MA 02114
Salony, Sole X, Alves CP, Dey-Guha I, Ritsma L, Boukhali M, Lee J-H, Chow-dhury J, Ross K, Haas W, Vasudevan S, Ramaswamy S. AKT inhibition promotes non-autonomous cancer cell survival. Mol Cancer Ther. 2015; in press.
Dey-Guha I, Alves CP, Yeh AC, Sa-lony, Sole X, Darp RA, Ramaswamy S. A mechanism for asymmetric cell division resulting in proliferative asynchronicity. Mol Cancer Res. 13:223-230, 2015.
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
Richard B. Simches Research Center
Directions to the Ramaswamy Lab.
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