Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease
Justin Lamb,1*Emily D. Crawford,1David Peck,1Joshua W. Modell,1Irene C. Blat,1Matthew J. Wrobel,1Jim Lerner,1Jean-Philippe Brunet,1Aravind Subramanian,1Kenneth N. Ross,1Michael Reich,1Haley Hieronymus,1,2Guo Wei,1,2Scott A. Armstrong,2,3Stephen J. Haggarty,1,4Paul A. Clemons,1Ru Wei,1Steven A. Carr,1Eric S. Lander,1,5,6Todd R. Golub1,2,3,5,7*
To pursue a systematic approach to the discovery of functionalconnections among diseases, genetic perturbation, and drug action,we have created the first installment of a reference collectionof gene-expression profiles from cultured human cells treatedwith bioactive small molecules, together with pattern-matchingsoftware to mine these data. We demonstrate that this "ConnectivityMap" resource can be used to find connections among small moleculessharing a mechanism of action, chemicals and physiological processes,and diseases and drugs. These results indicate the feasibilityof the approach and suggest the value of a large-scale communityConnectivity Map project.
1 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. 2 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. 3 Department of Medicine, Children's Hospital Boston, Boston, MA 02115, USA. 4 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02144, USA. 5 Harvard Medical School, Boston, MA 02115, USA. 6 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. 7 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Present address: University of California, San Francisco, CA94158, USA.
* To whom correspondence should be addressed. E-mail: golub{at}broad.harvard.edu, justin{at}broad.mit.edu
The editors suggest the following Related Resources on Science sites:
In Science Magazine
INTRODUCTION TO SPECIAL ISSUE
Barbara R. Jasny, Elizabeth Pennisi, and John Travis (29 September 2006) Science313 (5795), 1907.
[DOI: 10.1126/science.313.5795.1907] |Summary »|PDF »
In Science Signaling
EDITORS' CHOICE
Barbara R. Jasny (3 October 2006) Sci. STKE2006 (355), tw343.
[DOI: 10.1126/stke.3552006tw343] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
p38 Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR.
F. Farooq, S. Balabanian, X. Liu, M. Holcik, and A. MacKenzie (2009)
Hum. Mol. Genet.
18, 4035-4045
|Abstract »|Full Text »|PDF »
The p53 Family Protein p73 Provides New Insights into Cancer Chemosensitivity and Targeting.
P. Lunghi, A. Costanzo, L. Mazzera, V. Rizzoli, M. Levrero, and A. Bonati (2009)
Clin. Cancer Res.
15, 6495-6502
|Abstract »|Full Text »|PDF »
The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells.
S. Tardito, C. Isella, E. Medico, L. Marchio, E. Bevilacqua, M. Hatzoglou, O. Bussolati, and R. Franchi-Gazzola (2009)
J. Biol. Chem.
284, 24306-24319
|Abstract »|Full Text »|PDF »
Pathways of the Heart.
R. C. Deo and F. P. Roth (2009)
Circ Cardiovasc Genet
2, 303-305
|Full Text »|PDF »
HORMONOMETER: A Tool for Discerning Transcript Signatures of Hormone Action in the Arabidopsis Transcriptome.
D. Volodarsky, N. Leviatan, A. Otcheretianski, and R. Fluhr (2009)
Plant Physiology
150, 1796-1805
|Abstract »|Full Text »|PDF »
Systematizing Serendipity for Cardiovascular Drug Discovery.
P. J. Schlueter and R. T. Peterson (2009)
Circulation
120, 255-263
|Full Text »|PDF »
Probabilistic retrieval and visualization of biologically relevant microarray experiments.
J. Caldas, N. Gehlenborg, A. Faisal, A. Brazma, and S. Kaski (2009)
Bioinformatics
25, i145-i153
|Abstract »|Full Text »|PDF »
Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses.
D. K. Slonim, K. Koide, K. L. Johnson, U. Tantravahi, J. M. Cowan, Z. Jarrah, and D. W. Bianchi (2009)
PNAS
106, 9425-9429
|Abstract »|Full Text »|PDF »
Meta-mining of Neuroblastoma and Neuroblast Gene Expression Profiles Reveals Candidate Therapeutic Compounds.
K. De Preter, S. De Brouwer, T. Van Maerken, F. Pattyn, A. Schramm, A. Eggert, J. Vandesompele, and F. Speleman (2009)
Clin. Cancer Res.
15, 3690-3696
|Abstract »|Full Text »|PDF »
C. Swanton, B. Nicke, M. Schuett, A. C. Eklund, C. Ng, Q. Li, T. Hardcastle, A. Lee, R. Roy, P. East, et al. (2009)
PNAS
106, 8671-8676
|Abstract »|Full Text »|PDF »
Cyclodepsipeptide toxin promotes the degradation of Hsp90 client proteins through chaperone-mediated autophagy.
S. Shen, P. Zhang, M. A. Lovchik, Y. Li, L. Tang, Z. Chen, R. Zeng, D. Ma, J. Yuan, and Q. Yu (2009)
J. Cell Biol.
185, 629-639
|Abstract »|Full Text »|PDF »
Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose Deprivation.
S. Saito, A. Furuno, J. Sakurai, A. Sakamoto, H.-R. Park, K. Shin-ya, T. Tsuruo, and A. Tomida (2009)
Cancer Res.
69, 4225-4234
|Abstract »|Full Text »|PDF »
Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening.
H. G. Woo, E. S. Park, J.-S. Lee, Y.-H. Lee, T. Ishikawa, Y. J. Kim, and S. S. Thorgeirsson (2009)
Cancer Res.
69, 4059-4066
|Abstract »|Full Text »|PDF »
Relationship of Deregulated Signaling Converging onto mTOR with Prognosis and Classification of Lung Adenocarcinoma Shown by Two Independent In silico Analyses.
H. Ebi, S. Tomida, T. Takeuchi, C. Arima, T. Sato, T. Mitsudomi, Y. Yatabe, H. Osada, and T. Takahashi (2009)
Cancer Res.
69, 4027-4035
|Abstract »|Full Text »|PDF »
GS2: an efficiently computable measure of GO-based similarity of gene sets.
Hitting Cancer Where It Hurts Most: The RNAi Strategy to Discover Synthetic Lethal Interactions in Cancer.
R. L. Beijersbergen (2009)
Am. Assoc. Cancer Res. Educ. Book
2009, 249-252
|Full Text »|PDF »
Gene Expression Patterns in Mismatch Repair-Deficient Colorectal Cancers Highlight the Potential Therapeutic Role of Inhibitors of the Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway.
E. Vilar, B. Mukherjee, R. Kuick, L. Raskin, D. E. Misek, J. M.G. Taylor, T. J. Giordano, S. M. Hanash, E. R. Fearon, G. Rennert, et al. (2009)
Clin. Cancer Res.
15, 2829-2839
|Abstract »|Full Text »|PDF »
Identifying the proteins to which small-molecule probes and drugs bind in cells.
S.-E. Ong, M. Schenone, A. A. Margolin, X. Li, K. Do, M. K. Doud, D. R. Mani, L. Kuai, X. Wang, J. L. Wood, et al. (2009)
PNAS
106, 4617-4622
|Abstract »|Full Text »|PDF »
Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation.
H. B. Salvesen, S. L. Carter, M. Mannelqvist, A. Dutt, G. Getz, I. M. Stefansson, M. B. Raeder, M. L. Sos, I. B. Engelsen, J. Trovik, et al. (2009)
PNAS
106, 4834-4839
|Abstract »|Full Text »|PDF »
V600EBRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway.
C. A. Pratilas, B. S. Taylor, Q. Ye, A. Viale, C. Sander, D. B. Solit, and N. Rosen (2009)
PNAS
106, 4519-4524
|Abstract »|Full Text »|PDF »
HOXA9 is required for survival in human MLL-rearranged acute leukemias.
J. Faber, A. V. Krivtsov, M. C. Stubbs, R. Wright, T. N. Davis, M. van den Heuvel-Eibrink, C. M. Zwaan, A. L. Kung, and S. A. Armstrong (2009)
Blood
113, 2375-2385
|Abstract »|Full Text »|PDF »
Elucidating the Role of Gonadal Hormones in Sexually Dimorphic Gene Coexpression Networks.
A. van Nas, D. GuhaThakurta, S. S. Wang, N. Yehya, S. Horvath, B. Zhang, L. Ingram-Drake, G. Chaudhuri, E. E. Schadt, T. A. Drake, et al. (2009)
Endocrinology
150, 1235-1249
|Abstract »|Full Text »|PDF »
NS-398, ibuprofen, and cyclooxygenase-2 RNA interference produce significantly different gene expression profiles in prostate cancer cells.
M. John-Aryankalayil, S. T. Palayoor, D. Cerna, M. T. Falduto, S. R. Magnuson, and C. N. Coleman (2009)
Mol. Cancer Ther.
8, 261-273
|Abstract »|Full Text »|PDF »
A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities.
K. S. Garman, C. R. Acharya, E. Edelman, M. Grade, J. Gaedcke, S. Sud, W. Barry, A. M. Diehl, D. Provenzale, G. S. Ginsburg, et al. (2008)
PNAS
105, 19432-19437
|Abstract »|Full Text »|PDF »
Gene expression module-based chemical function similarity search.
Y. Li, P. Hao, S. Zheng, K. Tu, H. Fan, R. Zhu, G. Ding, C. Dong, C. Wang, X. Li, et al. (2008)
Nucleic Acids Res.
36, e137
|Abstract »|Full Text »|PDF »
Identification of a nonkinase target mediating cytotoxicity of novel kinase inhibitors.
P. Ross-Macdonald, H. de Silva, Q. Guo, H. Xiao, C.-Y. Hung, B. Penhallow, J. Markwalder, L. He, R. M. Attar, T.-a. Lin, et al. (2008)
Mol. Cancer Ther.
7, 3490-3498
|Abstract »|Full Text »|PDF »
Novel pathway compendium analysis elucidates mechanism of pro-angiogenic synthetic small molecule.
K. A. Wieghaus, E. P. Gianchandani, M. A. Paige, M. L. Brown, E. A. Botchwey, and J. A. Papin (2008)
Bioinformatics
24, 2384-2390
|Abstract »|Full Text »|PDF »
A Gene Signature-Based Approach Identifies mTOR as a Regulator of p73.
J. M. Rosenbluth, D. J. Mays, M. F. Pino, L. J. Tang, and J. A. Pietenpol (2008)
Mol. Cell. Biol.
28, 5951-5964
|Abstract »|Full Text »|PDF »
A genomic approach to identify molecular pathways associated with chemotherapy resistance.
R. F. Riedel, A. Porrello, E. Pontzer, E. J. Chenette, D. S. Hsu, B. Balakumaran, A. Potti, J. Nevins, and P. G. Febbo (2008)
Mol. Cancer Ther.
7, 3141-3149
|Abstract »|Full Text »|PDF »
Curcumin Inhibits Lung Cancer Cell Invasion and Metastasis through the Tumor Suppressor HLJ1.
H.-W. Chen, J.-Y. Lee, J.-Y. Huang, C.-C. Wang, W.-J. Chen, S.-F. Su, C.-W. Huang, C.-C. Ho, J. J.W. Chen, M.-F. Tsai, et al. (2008)
Cancer Res.
68, 7428-7438
|Abstract »|Full Text »|PDF »
Transforming Growth Factor {beta} Engages TACE and ErbB3 To Activate Phosphatidylinositol-3 Kinase/Akt in ErbB2-Overexpressing Breast Cancer and Desensitizes Cells to Trastuzumab.
S. E. Wang, B. Xiang, M. Guix, M. G. Olivares, J. Parker, C. H. Chung, A. Pandiella, and C. L. Arteaga (2008)
Mol. Cell. Biol.
28, 5605-5620
|Abstract »|Full Text »|PDF »
Insulin-Like Growth Factor-I Activates Gene Transcription Programs Strongly Associated With Poor Breast Cancer Prognosis.
C. J. Creighton, A. Casa, Z. Lazard, S. Huang, A. Tsimelzon, S. G. Hilsenbeck, C. K. Osborne, and A. V. Lee (2008)
J. Clin. Oncol.
26, 4078-4085
|Abstract »|Full Text »|PDF »
Cozzarelli Prize Winner@;DELIM@;From the Cover: The implications of human metabolic network topology for disease comorbidity.
D.-S. Lee, J. Park, K. A. Kay, N. A. Christakis, Z. N. Oltvai, and A.-L. Barabasi (2008)
PNAS
105, 9880-9885
|Abstract »|Full Text »|PDF »
Expression-based screening identifies the combination of histone deacetylase inhibitors and retinoids for neuroblastoma differentiation.
C. K. Hahn, K. N. Ross, I. M. Warrington, R. Mazitschek, C. M. Kanegai, R. D. Wright, A. L. Kung, T. R. Golub, and K. Stegmaier (2008)
PNAS
105, 9751-9756
|Abstract »|Full Text »|PDF »
Two strategies for gene regulation by promoter nucleosomes.
Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data.
D. C. Hassane, M. L. Guzman, C. Corbett, X. Li, R. Abboud, F. Young, J. L. Liesveld, M. Carroll, and C. T. Jordan (2008)
Blood
111, 5654-5662
|Abstract »|Full Text »|PDF »
Estrogen-Dependent Signaling in a Molecularly Distinct Subclass of Aggressive Prostate Cancer.
S. R. Setlur, K. D. Mertz, Y. Hoshida, F. Demichelis, M. Lupien, S. Perner, A. Sboner, Y. Pawitan, O. Andren, L. A. Johnson, et al. (2008)
J Natl Cancer Inst
100, 815-825
|Abstract »|Full Text »|PDF »
SNP panel identification assay (SPIA): a genetic-based assay for the identification of cell lines.
F. Demichelis, H. Greulich, J. A. Macoska, R. Beroukhim, W. R. Sellers, L. Garraway, and M. A. Rubin (2008)
Nucleic Acids Res.
36, 2446-2456
|Abstract »|Full Text »|PDF »
Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1{alpha} and oxidative phosphorylation.
Z. Arany, B. K. Wagner, Y. Ma, J. Chinsomboon, D. Laznik, and B. M. Spiegelman (2008)
PNAS
105, 4721-4726
|Abstract »|Full Text »|PDF »
Modeling Genomic Diversity and Tumor Dependency in Malignant Melanoma.
W. M. Lin, A. C. Baker, R. Beroukhim, W. Winckler, W. Feng, J. M. Marmion, E. Laine, H. Greulich, H. Tseng, C. Gates, et al. (2008)
Cancer Res.
68, 664-673
|Abstract »|Full Text »|PDF »
Revealing Targeted Therapy for Human Cancer by Gene Module Maps.
D. J. Wong, D. S.A. Nuyten, A. Regev, M. Lin, A. S. Adler, E. Segal, M. J. van de Vijver, and H. Y. Chang (2008)
Cancer Res.
68, 369-378
|Abstract »|Full Text »|PDF »
DBTSS: database of transcription start sites, progress report 2008.
H. Wakaguri, R. Yamashita, Y. Suzuki, S. Sugano, and K. Nakai (2008)
Nucleic Acids Res.
36, D97-D101
|Abstract »|Full Text »|PDF »
High-throughput screening for fatty acid uptake inhibitors in humanized yeast identifies atypical antipsychotic drugs that cause dyslipidemias.
H. Li, P. N. Black, A. Chokshi, A. Sandoval-Alvarez, R. Vatsyayan, W. Sealls, and C. C. DiRusso (2008)
J. Lipid Res.
49, 230-244
|Abstract »|Full Text »|PDF »
Current progress in network research: toward reference networks for key model organisms.
B. S. Srinivasan, N. H. Shah, J. A. Flannick, E. Abeliuk, A. F. Novak, and S. Batzoglou (2007)
Brief Bioinform
8, 318-332
|Abstract »|Full Text »|PDF »
Genetic Toxicity Assessment: Employing the Best Science for Human Safety Evaluation Part VII: Why Not Start with a Single Test: A Transformational Alternative to Genotoxicity Hazard and Risk Assessment.
W. W. Ku, J. Aubrecht, R. J. Mauthe, R. H. Schiestl, and A. J. Fornace Jr (2007)
Toxicol. Sci.
99, 20-25
|Abstract »|Full Text »|PDF »
Detecting genetic variation in microarray expression data.
J. A. Greenhall, M. A. Zapala, M. Caceres, O. Libiger, C. Barlow, N. J. Schork, and D. J. Lockhart (2007)
Genome Res.
17, 1228-1235
|Abstract »|Full Text »|PDF »
A Perspective on DNA Microarrays in Pathology Research and Practice.
Immune Signatures of Murine and Human Cancers Reveal Unique Mechanisms of Tumor Escape and New Targets for Cancer Immunotherapy.
R. E. Sadun, S. M. Sachsman, X. Chen, K. W. Christenson, W. Z. Morris, P. Hu, and A. L. Epstein (2007)
Clin. Cancer Res.
13, 4016-4025
|Abstract »|Full Text »|PDF »
Personalized Medicine for High Blood Pressure.
S. T. Turner, G. L. Schwartz, and E. Boerwinkle (2007)
Hypertension
50, 1-5
|Full Text »|PDF »
High-Throughput, High-Sensitivity Analysis of Gene Expression in Arabidopsis.
R. M. Kris, S. Felder, M. Deyholos, G. M. Lambert, J. Hinton, I. Botros, R. Martel, B. Seligmann, and D. W. Galbraith (2007)
Plant Physiology
144, 1256-1266
|Abstract »|Full Text »|PDF »
Connecting the Dots Using Gene-Expression Profiles.
S. R. Gullans (2006)
N. Engl. J. Med.
355, 2042-2044
|Full Text »|PDF »