ABSTRACT Multiple, complex molecular events characterize cancer development and progression1,2. Deciphering the molecular networks that distinguish organ-confined disease from metastatic

disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human

tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass

spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic

invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-_N_-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated

prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign

prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of

prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity. Access through your institution Buy or subscribe

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INTEGRATIVE PROTEOGENOMIC PROFILING OF HIGH-RISK PROSTATE CANCER SAMPLES FROM CHINESE PATIENTS INDICATES METABOLIC VULNERABILITIES AND DIAGNOSTIC BIOMARKERS Article 06 September 2024 SOX2

MEDIATES METABOLIC REPROGRAMMING OF PROSTATE CANCER CELLS Article 24 January 2022 PI3K-REGULATED GLYCINE N-METHYLTRANSFERASE IS REQUIRED FOR THE DEVELOPMENT OF PROSTATE CANCER Article Open

access 23 February 2022 CHANGE HISTORY * _ 05 JUNE 2013 Nature 457, 910–914 (2009); doi:10.1038/nature07762 In Fig. 4b of this Article, a typographical error was made in reporting sarcosine

levels in the DU145 cell line represented. The y axis values should be in the scale of 0–50 pmoles per 106 cells, rather than 0–500 pmoles per 106 cells. This error has been verified and

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Download references ACKNOWLEDGEMENTS We thank J. Granger for help in manuscript preparation, J. Siddiqui and R. Varambally for help with the clinical database, and A. Vellaichamy and S.

Pullela for technical assistance. We thank K. Pienta for access to metastatic prostate cancer samples from the University of Michigan Prostate SPORE rapid autopsy programme. This work is

supported in part by the Early Detection Research Network (A.M.C., J.T.W.), National Institutes of Health (A.S., S.P., J.B., T.M.R., D.G., G.S.O. and A.M.C.) and an MTTC grant (G.S.O. and

A.S.). A.M.C. is supported by a Clinical Translational Science Award from the Burroughs Welcome Foundation. A.S. is supported by a grant from the Fund for Discovery of the University of

Michigan Comprehensive Cancer Center. L.M.P. is supported by the University of Michigan Cancer Biostatistics Training Grant. A.M.C and S.P. are supported by the Doris Duke Charitable

Foundation. AUTHOR CONTRIBUTIONS A.S., L.M.P. and A.M.C. wrote the manuscript. A.S. and A.M.C. conceptualized, designed and interpreted the data. L.M.P., R.J.L., S.K.-S., D.G. and D.C.A.

performed data analysis. T.M.R., G.S.O., J.B. S.P., J.R.S., A.B. and C.B. carried out the mass spectrometry studies. A.P.K., J.Y., Q.C., B.L., Y.L., M.K.N., A.A., X.C. and S.V. performed

biochemical experiments. R.M., B.H., A.M.C. and J.T.W. coordinated the clinical and pathology components of the study. AUTHOR INFORMATION Author notes * Laila M. Poisson, Thekkelnaycke M.

Rajendiran and Amjad P. Khan: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * The Michigan Center for Translational Pathology,, Arun Sreekumar, Thekkelnaycke M.

Rajendiran, Amjad P. Khan, Qi Cao, Jindan Yu, Bharathi Laxman, Rohit Mehra, Robert J. Lonigro, Yong Li, Shanker Kalyana-Sundaram, Bo Han, Xuhong Cao, Sooryanarayana Varambally, Christopher

Beecher & Arul M. Chinnaiyan * Center for Computational Medicine and Biology,, Arun Sreekumar, Gilbert S. Omenn, Subramaniam Pennathur, Christopher Beecher & Arul M. Chinnaiyan *

Department of Pathology,, Arun Sreekumar, Thekkelnaycke M. Rajendiran, Amjad P. Khan, Qi Cao, Jindan Yu, Bharathi Laxman, Rohit Mehra, Yong Li, Shanker Kalyana-Sundaram, Bo Han, Xuhong Cao, 

Sooryanarayana Varambally, Christopher Beecher & Arul M. Chinnaiyan * The Comprehensive Cancer Center,, Arun Sreekumar, Robert J. Lonigro, Mukesh K. Nyati, Debashis Ghosh, Subramaniam

Pennathur, John T. Wei, Sooryanarayana Varambally & Arul M. Chinnaiyan * Department of Biostatistics,, Laila M. Poisson & Debashis Ghosh * Department of Radiation Oncology,, Mukesh

K. Nyati & Aarif Ahsan * Department of Internal Medicine,, Jaeman Byun, Gilbert S. Omenn & Subramaniam Pennathur * Department of Human Genetics,, Gilbert S. Omenn * Department of

Urology,, John T. Wei & Arul M. Chinnaiyan * Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA , Arul M. Chinnaiyan * Department of

Statistics and Huck Institute of Life Sciences, Penn State University, Pennsylvania 16802, USA, Debashis Ghosh * Metabolon, Inc. 800 Capitola Drive, Suite 1 Durham, North Carolina 27713, USA

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COMPETING INTERESTS C.B. was previously an employee of Metabolon. C.B., D.C.A., J.R.S. and A.B. own equity in Metabolon. A.M.C. joined the Scientific Advisory Board of Metabolon in July

2008. The University of Michigan has licensed the diagnostic field of use of the metabolomic biomarkers discussed in this manuscript to Metabolon (A.M.C. and A.S. are named as inventors).

SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains Supplementary Methods, a Supplementary Discussion, Supplementary References and Supplementary Tables 1-10 (PDF 540 kb)

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profiles delineate potential role for sarcosine in prostate cancer progression. _Nature_ 457, 910–914 (2009). https://doi.org/10.1038/nature07762 Download citation * Received: 09 October

2008 * Accepted: 06 January 2009 * Published: 01 February 2009 * Issue Date: 12 February 2009 * DOI: https://doi.org/10.1038/nature07762 SHARE THIS ARTICLE Anyone you share the following

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