Abstract

The genome of pancreatic ductal adenocarcinoma (PDAC) frequently contains deletions of tumour suppressor gene loci, most notably SMAD4, which is homozygously deleted in nearly one-third of cases1. As loss of neighbouring housekeeping genes can confer collateral lethality, we sought to determine whether loss of the metabolic gene malic enzyme 2 (ME2) in the SMAD4 locus would create cancer-specific metabolic vulnerability upon targeting of its paralogous isoform ME3. The mitochondrial malic enzymes (ME2 and ME3) are oxidative decarboxylases that catalyse the conversion of malate to pyruvate and are essential for NADPH regeneration and reactive oxygen species homeostasis2,3. Here we show that ME3 depletion selectively kills ME2-null PDAC cells in a manner consistent with an essential function for ME3 in ME2-null cancer cells. Mechanistically, integrated metabolomic and molecular investigation of cells deficient in mitochondrial malic enzymes revealed diminished NADPH production and consequent high levels of reactive oxygen species. These changes activate AMP activated protein kinase (AMPK), which in turn directly suppresses sterol regulatory element-binding protein 1 (SREBP1)-directed transcription of its direct targets including the BCAT2 branched-chain amino acid transaminase 2) gene. BCAT2 catalyses the transfer of the amino group from branched-chain amino acids to α-ketoglutarate (α-KG)4 thereby regenerating glutamate, which functions in part to support de novo nucleotide synthesis. Thus, mitochondrial malic enzyme deficiency, which results in impaired NADPH production, provides a prime ‘collateral lethality’ therapeutic strategy for the treatment of a substantial fraction of patients diagnosed with this intractable disease.

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Acknowledgements

We thank T. Tieu for vector cloning; the MD Anderson core facilities, including K. Dunner Jr for High Resolution Electron Microscopy Facility, Sequencing and Microarray Facility (SMF), Flow Cytometry and Cellular Imaging Core Facility; S. Jiang and Z. Xu for assistance in maintenance of mouse colonies; Z. Lu for discussion; and D. Spring for editing. This study was supported by NCI P01 CA117969 grant (R.A.D.); UT Star award (R.A.D.); CPRIT grant RP140612 (R.A.D.); DOD Postdoctoral research fellowship W81XWH-14-1-0429 (P.D.); MD Anderson Bridge Fund (R.A.D.); St. Louis Ovarian Cancer Awareness Research Grant (D.N.) and Odyssey Fellowships at MD Anderson (D.Z., T.G.). The MD Anderson core facilities are supported by NIH P30 CA16672.

Author information

Author notes

    • Prasenjit Dey
    •  & Joelle Baddour

    These authors contributed equally to this work.

Affiliations

  1. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Prasenjit Dey
    • , Wen-Ting Liao
    • , Zangdao Lan
    • , Alina Chen
    • , Di Zhao
    • , Y. Alan Wang
    •  & Ronald A. DePinho
  2. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Prasenjit Dey
    • , Chia Chin Wu
    • , Tony Gutschner
    • , Edward Chang
    • , Giannicola Genovese
    • , Andrea Viale
    • , Giulio Draetta
    •  & Y. Alan Wang
  3. Department of Chemical and Biomolecular Engineering, Department of Bioengineering, Rice University, 6100 Main Street, Houston, Texas 77005, USA

    • Joelle Baddour
    • , Abhinav Achreja
    • , Lifeng Yang
    • , Jiyoon Lee
    •  & Deepak Nagrath
  4. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Florian Muller
    •  & Nikunj Satani
  5. Department of Pathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Huamin Wang
  6. Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Yaan Kang
    •  & Jason Fleming
  7. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Edward Chang
    •  & Giulio Draetta
  8. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Haoqiang Ying
    •  & Giulio Draetta
  9. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Anirban Maitra
  10. Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Anirban Maitra

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Contributions

P.D., Y.A.W., D.N. and R.A.D. designed the studies, interpreted the data and wrote the manuscript; P.D. performed all experiments; J.B. performed experiments and analysis of metabolite isotope tracing, Seahorse and UPLC; A.A. and L.Y. conducted metabolomics data analysis; C.C.W. performed bioinformatics analysis; W.-T.L. and H.W. conducted tissue microarray analysis; Z.L. conducted ChIP analysis; T.G. was responsible for ME2 CRISPR design and cloning; Y.K., J.F. and A.V. contributed essential reagents and resources; F.M., G.G., H.Y., G.D. and A.M. provided intellectual input; A.C., N.S., D.Z., Y.K., J.L. and E.C. provided technical support.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Y. Alan Wang or Deepak Nagrath or Ronald A. DePinho.

Reviewer Information Nature thanks C. Van Dang, A. Trumpp and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature21052

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