• A Corrigendum to this article was published on 12 June 2013


Cancer cells have metabolic dependencies that distinguish them from their normal counterparts1. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes2. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumours.

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We would like to thank D. Anastasiou for advice and helpful comments on the manuscript; M. Yuan and S. Breitkopf for technical help with mass spectrometry experiments; J. Erickson, R. Cerione and J. Escobedo for the GLS inhibitors. Grant support derives from the Dana Farber Cancer Institute (A.C.K.), National Cancer Institute Grant R01 CA157490 (A.C.K.), Kimmel Scholar Award (A.C.K.), AACR-PanCAN Career Development Award (A.C.K.), NIH grants T32 CA009382-26 (H.Y.) and P01 CA117969 (L.C.C. and R.A.D.). C.A.L. is the Amgen Fellow of the Damon Runyon Cancer Research Foundation (DRG-2056-10). NIH grants 5P01CA120964-05 and Dana–Farber/Harvard Cancer Center Support Grant 5P30CA006516-46 (J.M.A.).

Author information

Author notes

    • Jaekyoung Son
    •  & Costas A. Lyssiotis

    These authors contributed equally to this work.

    • Costas A. Lyssiotis
    • , Edouard Mullarky
    •  & Lewis C. Cantley

    Present address: Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.


  1. Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Jaekyoung Son
    • , Xiaoxu Wang
    •  & Alec C. Kimmelman
  2. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Costas A. Lyssiotis
    • , Edouard Mullarky
    • , Ng Shyh-Chang
    •  & Lewis C. Cantley
  3. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA

    • Costas A. Lyssiotis
    • , Edouard Mullarky
    • , John M. Asara
    •  & Lewis C. Cantley
  4. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Haoqiang Ying
    • , Sujun Hua
    •  & Ronald A. DePinho
  5. Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Matteo Ligorio
    •  & Cristina R. Ferrone
  6. Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Rushika M. Perera
    •  & Nabeel Bardeesy
  7. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Children’s Hospital Boston and Dana Farber Cancer Institute, Boston, Massachusetts 02130, USA

    • Ng Shyh-Chang
  8. Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Ya’an Kang
    •  & Jason B. Fleming
  9. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA

    • John M. Asara
  10. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Marcia C. Haigis


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J.S., C.A.L., L.C.C. and A.C.K. designed the study, interpreted the data and wrote the manuscript. J.S., C.A.L., H.Y. and X.W. performed the experiments. J.M.A., E.M. and N.S. helped with the metabolomic studies and with S.H., M.C.H. and R.A.D. assisted in data interpretation. M.L., R.M.P., C.R.F., Y.K., N.B. and J.B.F. developed essential reagents and resources.

Competing interests

A.C.K. is a Consultant for Forma Therapeutics. L.C.C. owns equity in, receives compensation from Agios Pharmaceuticals, and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals. Agios Pharmaceuticals is identifying metabolic pathways of cancer cells and developing drugs to inhibit such enzymes in order to disrupt tumour cell growth and survival.

Corresponding authors

Correspondence to Lewis C. Cantley or Alec C. Kimmelman.

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    Supplementary Information

    This file contains Supplementary Figures 1-21 and Primer Sequences for qRT-PCR.

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