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6
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Gast CE, Silk AD, Zarour L, Riegler L, Burkhart JG, Gustafson KT, Parappilly MS, Roh-Johnson M, Goodman JR, Olson B, Schmidt M, Swain JR, Davies PS, Shasthri V, Iizuka S, Flynn P, Watson S, Korkola J, Courtneidge SA, Fischer JM, Jaboin J, Billingsley KG, Lopez CD, Burchard J, Gray J, Coussens LM, Sheppard BC, Wong MH. Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival. SCIENCE ADVANCES 2018; 4:eaat7828. [PMID: 30214939 PMCID: PMC6135550 DOI: 10.1126/sciadv.aat7828] [Citation(s) in RCA: 212] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 08/01/2018] [Indexed: 05/06/2023]
Abstract
High lethality rates associated with metastatic cancer highlight an urgent medical need for improved understanding of biologic mechanisms driving metastatic spread and identification of biomarkers predicting late-stage progression. Numerous neoplastic cell intrinsic and extrinsic mechanisms fuel tumor progression; however, mechanisms driving heterogeneity of neoplastic cells in solid tumors remain obscure. Increased mutational rates of neoplastic cells in stressed environments are implicated but cannot explain all aspects of tumor heterogeneity. We present evidence that fusion of neoplastic cells with leukocytes (for example, macrophages) contributes to tumor heterogeneity, resulting in cells exhibiting increased metastatic behavior. Fusion hybrids (cells harboring hematopoietic and epithelial properties) are readily detectible in cell culture and tumor-bearing mice. Further, hybrids enumerated in peripheral blood of human cancer patients correlate with disease stage and predict overall survival. This unique population of neoplastic cells provides a novel biomarker for tumor staging, as well as a potential therapeutic target for intervention.
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Affiliation(s)
- Charles E. Gast
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Alain D. Silk
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Luai Zarour
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Lara Riegler
- Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
| | - Joshua G. Burkhart
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Kyle T. Gustafson
- Center for Early Detection Advanced Research, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA
| | - Michael S. Parappilly
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Minna Roh-Johnson
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA
| | - James R. Goodman
- Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Brennan Olson
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Mark Schmidt
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - John R. Swain
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Paige S. Davies
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Vidya Shasthri
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Shinji Iizuka
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Patrick Flynn
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Spencer Watson
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - James Korkola
- Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Sara A. Courtneidge
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Jared M. Fischer
- Center for Early Detection Advanced Research, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA
| | - Jerry Jaboin
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR 97239, USA
| | - Kevin G. Billingsley
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Charles D. Lopez
- Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Julja Burchard
- Department of Computational Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Joe Gray
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Lisa M. Coussens
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Brett C. Sheppard
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Melissa H. Wong
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Corresponding author.
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9
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Watson SS, Dane M, Chin K, Tatarova Z, Liu M, Liby T, Thompson W, Smith R, Nederlof M, Bucher E, Kilburn D, Whitman M, Sudar D, Mills GB, Heiser LM, Jonas O, Gray JW, Korkola JE. Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes. Cell Syst 2018; 6:329-342.e6. [PMID: 29550255 PMCID: PMC5927625 DOI: 10.1016/j.cels.2018.02.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 08/16/2017] [Accepted: 02/02/2018] [Indexed: 01/19/2023]
Abstract
Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ~2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-β1 (NRG1β), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Breast Neoplasms/drug therapy
- Cell Line, Tumor
- Databases, Genetic
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Enzyme Inhibitors/pharmacology
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Genes, erbB-2/drug effects
- Genes, erbB-2/genetics
- Genes, erbB-2/physiology
- High-Throughput Screening Assays/methods
- Humans
- Lapatinib/pharmacology
- MCF-7 Cells
- Mice
- Protein Kinase Inhibitors/pharmacology
- Protein-Tyrosine Kinases/antagonists & inhibitors
- Proto-Oncogene Proteins c-met/antagonists & inhibitors
- Quinazolines/pharmacology
- Quinolines/pharmacology
- Receptor, ErbB-2/antagonists & inhibitors
- Receptor, ErbB-3/antagonists & inhibitors
- Signal Transduction/drug effects
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/physiology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Spencer S Watson
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Mark Dane
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Koei Chin
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Zuzana Tatarova
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Moqing Liu
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Tiera Liby
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Wallace Thompson
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Rebecca Smith
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Michel Nederlof
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Quantitative Imaging Systems LLC, 1410 NW Kearney Street, #1114, Portland, OR 97209, USA
| | - Elmar Bucher
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - David Kilburn
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Matthew Whitman
- Department of Radiology, Brigham & Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA
| | - Damir Sudar
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Quantitative Imaging Systems LLC, 1410 NW Kearney Street, #1114, Portland, OR 97209, USA
| | - Gordon B Mills
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Laura M Heiser
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Oliver Jonas
- Department of Radiology, Brigham & Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA
| | - Joe W Gray
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
| | - James E Korkola
- Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
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10
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Keenan AB, Jenkins SL, Jagodnik KM, Koplev S, He E, Torre D, Wang Z, Dohlman AB, Silverstein MC, Lachmann A, Kuleshov MV, Ma'ayan A, Stathias V, Terryn R, Cooper D, Forlin M, Koleti A, Vidovic D, Chung C, Schürer SC, Vasiliauskas J, Pilarczyk M, Shamsaei B, Fazel M, Ren Y, Niu W, Clark NA, White S, Mahi N, Zhang L, Kouril M, Reichard JF, Sivaganesan S, Medvedovic M, Meller J, Koch RJ, Birtwistle MR, Iyengar R, Sobie EA, Azeloglu EU, Kaye J, Osterloh J, Haston K, Kalra J, Finkbiener S, Li J, Milani P, Adam M, Escalante-Chong R, Sachs K, Lenail A, Ramamoorthy D, Fraenkel E, Daigle G, Hussain U, Coye A, Rothstein J, Sareen D, Ornelas L, Banuelos M, Mandefro B, Ho R, Svendsen CN, Lim RG, Stocksdale J, Casale MS, Thompson TG, Wu J, Thompson LM, Dardov V, Venkatraman V, Matlock A, Van Eyk JE, Jaffe JD, Papanastasiou M, Subramanian A, Golub TR, Erickson SD, Fallahi-Sichani M, Hafner M, Gray NS, Lin JR, Mills CE, Muhlich JL, Niepel M, Shamu CE, Williams EH, Wrobel D, Sorger PK, Heiser LM, Gray JW, Korkola JE, Mills GB, LaBarge M, Feiler HS, Dane MA, Bucher E, Nederlof M, Sudar D, Gross S, et alKeenan AB, Jenkins SL, Jagodnik KM, Koplev S, He E, Torre D, Wang Z, Dohlman AB, Silverstein MC, Lachmann A, Kuleshov MV, Ma'ayan A, Stathias V, Terryn R, Cooper D, Forlin M, Koleti A, Vidovic D, Chung C, Schürer SC, Vasiliauskas J, Pilarczyk M, Shamsaei B, Fazel M, Ren Y, Niu W, Clark NA, White S, Mahi N, Zhang L, Kouril M, Reichard JF, Sivaganesan S, Medvedovic M, Meller J, Koch RJ, Birtwistle MR, Iyengar R, Sobie EA, Azeloglu EU, Kaye J, Osterloh J, Haston K, Kalra J, Finkbiener S, Li J, Milani P, Adam M, Escalante-Chong R, Sachs K, Lenail A, Ramamoorthy D, Fraenkel E, Daigle G, Hussain U, Coye A, Rothstein J, Sareen D, Ornelas L, Banuelos M, Mandefro B, Ho R, Svendsen CN, Lim RG, Stocksdale J, Casale MS, Thompson TG, Wu J, Thompson LM, Dardov V, Venkatraman V, Matlock A, Van Eyk JE, Jaffe JD, Papanastasiou M, Subramanian A, Golub TR, Erickson SD, Fallahi-Sichani M, Hafner M, Gray NS, Lin JR, Mills CE, Muhlich JL, Niepel M, Shamu CE, Williams EH, Wrobel D, Sorger PK, Heiser LM, Gray JW, Korkola JE, Mills GB, LaBarge M, Feiler HS, Dane MA, Bucher E, Nederlof M, Sudar D, Gross S, Kilburn DF, Smith R, Devlin K, Margolis R, Derr L, Lee A, Pillai A. The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations. Cell Syst 2018; 6:13-24. [PMID: 29199020 PMCID: PMC5799026 DOI: 10.1016/j.cels.2017.11.001] [Show More Authors] [Citation(s) in RCA: 283] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 09/13/2017] [Accepted: 11/01/2017] [Indexed: 12/19/2022]
Abstract
The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies. Perturbations under study include drugs, genetic perturbations, tissue micro-environments, antibodies, and disease-causing mutations. Responses to perturbations are measured by transcript profiling, mass spectrometry, cell imaging, and biochemical methods, among other assays. The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders. This Perspective describes LINCS technologies, datasets, tools, and approaches to data accessibility and reusability.
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Affiliation(s)
- Alexandra B Keenan
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sherry L Jenkins
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Kathleen M Jagodnik
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Simon Koplev
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Edward He
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Denis Torre
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Zichen Wang
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Anders B Dohlman
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Moshe C Silverstein
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Alexander Lachmann
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Maxim V Kuleshov
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Avi Ma'ayan
- BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Vasileios Stathias
- BD2K-LINCS DCIC, Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33146, USA
| | - Raymond Terryn
- BD2K-LINCS DCIC, Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33146, USA
| | - Daniel Cooper
- BD2K-LINCS DCIC, Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33146, USA
| | - Michele Forlin
- BD2K-LINCS DCIC, Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33146, USA
| | - Amar Koleti
- BD2K-LINCS DCIC, Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33146, USA
| | - Dusica Vidovic
- BD2K-LINCS DCIC, Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33146, USA
| | - Caty Chung
- BD2K-LINCS DCIC, Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33146, USA
| | - Stephan C Schürer
- BD2K-LINCS DCIC, Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33146, USA
| | - Jouzas Vasiliauskas
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Marcin Pilarczyk
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Behrouz Shamsaei
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Mehdi Fazel
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Yan Ren
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Wen Niu
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Nicholas A Clark
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Shana White
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Naim Mahi
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Lixia Zhang
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Michal Kouril
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - John F Reichard
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Siva Sivaganesan
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Mario Medvedovic
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Jaroslaw Meller
- BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA
| | - Rick J Koch
- DToxS, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Marc R Birtwistle
- DToxS, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ravi Iyengar
- DToxS, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Eric A Sobie
- DToxS, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Evren U Azeloglu
- DToxS, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Julia Kaye
- NeuroLINCS, Gladstone Institute of Neurological Disease and the Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA 94158, USA
| | - Jeannette Osterloh
- NeuroLINCS, Gladstone Institute of Neurological Disease and the Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA 94158, USA
| | - Kelly Haston
- NeuroLINCS, Gladstone Institute of Neurological Disease and the Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA 94158, USA
| | - Jaslin Kalra
- NeuroLINCS, Gladstone Institute of Neurological Disease and the Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA 94158, USA
| | - Steve Finkbiener
- NeuroLINCS, Gladstone Institute of Neurological Disease and the Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA 94158, USA
| | - Jonathan Li
- NeuroLINCS, Department of Biological Engineering, MIT, Cambridge, MA 02142, USA
| | - Pamela Milani
- NeuroLINCS, Department of Biological Engineering, MIT, Cambridge, MA 02142, USA
| | - Miriam Adam
- NeuroLINCS, Department of Biological Engineering, MIT, Cambridge, MA 02142, USA
| | | | - Karen Sachs
- NeuroLINCS, Department of Biological Engineering, MIT, Cambridge, MA 02142, USA
| | - Alex Lenail
- NeuroLINCS, Department of Biological Engineering, MIT, Cambridge, MA 02142, USA
| | - Divya Ramamoorthy
- NeuroLINCS, Department of Biological Engineering, MIT, Cambridge, MA 02142, USA
| | - Ernest Fraenkel
- NeuroLINCS, Department of Biological Engineering, MIT, Cambridge, MA 02142, USA
| | - Gavin Daigle
- NeuroLINCS, Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Uzma Hussain
- NeuroLINCS, Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Alyssa Coye
- NeuroLINCS, Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Jeffrey Rothstein
- NeuroLINCS, Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Dhruv Sareen
- NeuroLINCS, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Loren Ornelas
- NeuroLINCS, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Maria Banuelos
- NeuroLINCS, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Berhan Mandefro
- NeuroLINCS, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ritchie Ho
- NeuroLINCS, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Clive N Svendsen
- NeuroLINCS, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ryan G Lim
- NeuroLINCS, Departments of Psychiatry and Human Behavior and Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697, USA
| | - Jennifer Stocksdale
- NeuroLINCS, Departments of Psychiatry and Human Behavior and Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697, USA
| | - Malcolm S Casale
- NeuroLINCS, Departments of Psychiatry and Human Behavior and Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697, USA
| | - Terri G Thompson
- NeuroLINCS, Departments of Psychiatry and Human Behavior and Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697, USA
| | - Jie Wu
- NeuroLINCS, Departments of Psychiatry and Human Behavior and Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697, USA
| | - Leslie M Thompson
- NeuroLINCS, Departments of Psychiatry and Human Behavior and Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697, USA
| | - Victoria Dardov
- NeuroLINCS, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | | | - Andrea Matlock
- NeuroLINCS, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | | | - Jacob D Jaffe
- LINCS PCCSE, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | | | - Aravind Subramanian
- LINCS Center for Transcriptomics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Todd R Golub
- LINCS Center for Transcriptomics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Sean D Erickson
- HMS LINCS Center, Harvard Medical School, Boston, MA 02115, USA
| | | | - Marc Hafner
- HMS LINCS Center, Harvard Medical School, Boston, MA 02115, USA
| | | | - Jia-Ren Lin
- HMS LINCS Center, Harvard Medical School, Boston, MA 02115, USA
| | - Caitlin E Mills
- HMS LINCS Center, Harvard Medical School, Boston, MA 02115, USA
| | | | - Mario Niepel
- HMS LINCS Center, Harvard Medical School, Boston, MA 02115, USA
| | | | | | - David Wrobel
- HMS LINCS Center, Harvard Medical School, Boston, MA 02115, USA
| | - Peter K Sorger
- HMS LINCS Center, Harvard Medical School, Boston, MA 02115, USA
| | - Laura M Heiser
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Joe W Gray
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - James E Korkola
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Gordon B Mills
- MEP-LINCS Center, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mark LaBarge
- MEP-LINCS Center, Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, CA 91011, USA; MEP-LINCS Center, Center for Cancer Biomarkers Research, University of Bergen, Bergen 5009, Norway
| | - Heidi S Feiler
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Mark A Dane
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Elmar Bucher
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Michel Nederlof
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA; MEP-LINCS Center, Quantitative Imaging Systems LLC, Portland, OR 97239, USA
| | - Damir Sudar
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA; MEP-LINCS Center, Quantitative Imaging Systems LLC, Portland, OR 97239, USA
| | - Sean Gross
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - David F Kilburn
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Rebecca Smith
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Kaylyn Devlin
- MEP-LINCS Center, Oregon Health & Science University, Portland, OR 97239, USA
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