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Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development

Nature Medicine volume 20, pages 1193–1198 (2014)Cite this article

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Abstract

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months1. PDAC has been linked with obesity and glucose intolerance2,3,4, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.

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Figure 1: Plasma metabolites and risk of future pancreatic cancer diagnosis.
Figure 2: Plasma BCAA levels are elevated during subclinical disease.
Figure 3: BCAA elevations are derived from a long-term pool of amino acids.

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Acknowledgements

We would like to acknowledge A. Deik and K. Bullock of the Broad Institute for assistance with LC-MS sample analyses and the Tang Histology facility in the Koch Institute Swanson Biotechnology Center for assistance processing mouse tissues. Cambridge Isotope Laboratories supplied 13C-BCAA diets for mouse labeling studies. We would like to thank C. Newgard and A. Goldberg for their thoughtful discussions regarding this manuscript. We would also like to thank the participants and staff of the Health Professionals Follow-Up Study (HPFS), Nurses' Health Study (NHS), Physicians' Health Study I (PHS) and Women's Health Initiative-Observational Study (WHI-OS) for their contributions as well as the cancer registries of the following states for their help: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Indiana, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington and Wyoming. NHS and HPFS are supported by US National Institutes of Health (NIH) grants P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, R01 CA49449 and 1UM1 CA167552. PHS is supported by NIH grants CA 97193, CA 34944, CA 40360, HL 26490 and HL 34595. The WHI program is funded by the NIH through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. We acknowledge additional support from grant F30 CA183474 to J.R.M.; from a Nestle Research Center award to the Broad Institute; from R01 DK081572 grant to T.J.W. and R.E.G.; from the Robert T. and Judith B. Hale Fund for Pancreatic Cancer, Perry S. Levy Fund for Gastrointestinal Cancer Research and Pappas Family Research Fund for Pancreatic Cancer to C.S.F.; from the Burroughs Wellcome Fund, Damon Runyon Cancer Research Foundation, the Smith Family and the Stern Family to M.G.V.H.; and from NIH/NCI grant K07 CA140790, the American Society of Clinical Oncology Conquer Cancer Foundation, the Howard Hughes Medical Institute and Promises for Purple to B.M.W. M.G.V.H. additionally acknowledges support from P30-CA14051 and P01-CA117969, and major support for this project was provided by the Howard Hughes Medical Institute to B.M.W. and the Lustgarten Foundation to C.S.F., M.G.V.H. and B.M.W.

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Author notes

  1. Jared R Mayers, Chen Wu and Clary B Clish: These authors contributed equally to this work.

Authors and Affiliations

  1. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Jared R Mayers, Margaret E Torrence, Brian P Fiske, Shawn M Davidson, Thales Papagiannakopoulos, Talya L Dayton & Matthew G Vander Heiden

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Jared R Mayers, Margaret E Torrence, Brian P Fiske, Shawn M Davidson, Thales Papagiannakopoulos, Talya L Dayton & Matthew G Vander Heiden

  3. Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    Chen Wu

  4. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

    Chen Wu, Chen Yuan, Shuji Ogino, Zhi Rong Qian, Douglas A Rubinson, Charles S Fuchs, Matthew G Vander Heiden & Brian M Wolpin

  5. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA

    Chen Wu, Peter Kraft, Shelley S Tworoger, Shuji Ogino, Meir J Stampfer, Edward L Giovannucci, Jing Ma, Howard D Sesso & JoAnn E Manson

  6. Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA

    Clary B Clish, Amanda Souza, Kerry Pierce, Robert E Gerszten & Matthew G Vander Heiden

  7. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

    Peter Kraft

  8. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Ying Bao, Mary K Townsend, Shelley S Tworoger, Meir J Stampfer, Edward L Giovannucci, Jing Ma, JoAnn E Manson & Charles S Fuchs

  9. Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Annan Yang & Alec C Kimmelman

  10. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Shuji Ogino

  11. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA

    Meir J Stampfer & Edward L Giovannucci

  12. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Howard D Sesso, John M Gaziano & JoAnn E Manson

  13. Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA

    John M Gaziano

  14. University of Washington School of Nursing, Seattle, Washington, USA

    Barbara B Cochrane

  15. Department of Epidemiology, Brown University, Providence, Rhode Island, USA

    Simin Liu

  16. Department of Medicine, Brown University, Providence, Rhode Island, USA

    Simin Liu

  17. Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA

    Jean Wactawski-Wende

  18. Department of Oncology, McGill University, Montreal, Quebec, Canada

    Michael N Pollak

  19. Department of Medicine, McGill University, Montreal, Quebec, Canada

    Michael N Pollak

  20. Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee, USA

    Thomas J Wang

  21. Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Robert E Gerszten

  22. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Brian M Wolpin

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  1. Jared R Mayers
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  2. Chen Wu
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  3. Clary B Clish
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Contributions

All authors participated in the analysis and interpretation of data. C.W., C.B.C., P.K., C.Y., Y.B., M.K.T. and B.M.W. performed the statistical analyses of the human data. C.B.C., M.K.T., S.S.T., T.J.W., R.E.G. and B.M.W. evaluated the platform for analysis of plasma metabolites in large cohort studies. C.B.C., J.R.M., A.S. and K.P. performed metabolite profiling experiments. P.K., Y.B., M.K.T., S.S.T., S.O., M.J.S., E.L.G., Z.R.Q., D.A.R., J.M., H.D.S., J.M.G., B.B.C., S.L., J.W.-W., J.E.M., M.N.P. and C.S.F. assisted in data acquisition, management and interpretation from the four cohort studies. J.R.M. and M.E.T. conducted all mouse experiments with assistance from B.P.F., S.M.D., T.P., A.Y., T.L.D. and A.C.K. C.W., C.B.C., J.R.M., C.S.F., M.G.V.H. and B.M.W. designed the study and drafted the manuscript with input from all authors.

Corresponding authors

Correspondence to Matthew G Vander Heiden or Brian M Wolpin.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

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Supplementary Tables 1–6 and Supplementary Figures 1–9 (PDF 46182 kb)

Supplementary Note

Tables S1–S7 and Figure S1 (DOC 527 kb)

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Mayers, J., Wu, C., Clish, C. et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 20, 1193–1198 (2014). https://doi.org/10.1038/nm.3686

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