During the progression of pancreatic ductal adenocarcinoma (PDAC), heterogeneous subclonal populations emerge that drive primary tumor growth, regional spread, distant metastasis, and patient death. However, the genetics of metastases largely reflects that of the primary tumor in untreated patients, and PDAC driver mutations are shared by all subclones. This raises the possibility that an epigenetic process might operate during metastasis. Here we report large-scale reprogramming of chromatin modifications during the natural evolution of distant metastasis. Changes were targeted to thousands of large chromatin domains across the genome that collectively specified malignant traits, including euchromatin and large organized chromatin histone H3 lysine 9 (H3K9)-modified (LOCK) heterochromatin. Remarkably, distant metastases co-evolved a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP), and oxPPP inhibition selectively reversed reprogrammed chromatin, malignant gene expression programs, and tumorigenesis. These findings suggest a model whereby linked metabolic–epigenetic programs are selected for enhanced tumorigenic fitness during the evolution of distant metastasis.

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We thank J. Zacharias for technical assistance with sample processing and members of the Johns Hopkins DNA sequencing core facility for ChIP–seq on SOLiD formats. This work was supported by NIH grant CA38548 (A.P.F.), NIH grants CA140599 and CA179991 (C.A.I.-D.), the AACR Pancreatic Cancer Action Network Pathway to Leadership grant (O.G.M.), the Vanderbilt GI SPORE (O.G.M.), the Vanderbilt–Ingram Cancer Center (O.G.M.), and NIH grant CA180682 (A.M.-M.).

Author information

Author notes

    • Oliver G McDonald
    •  & Xin Li

    These authors contributed equally to this work.


  1. Department of Pathology, Microbiology and Immunology, Vanderbilt–Ingram Cancer Center, and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Oliver G McDonald
    • , Anna E Word
    • , Sonoko Natsume
    •  & Kimberly M Stauffer
  2. Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Xin Li
    • , Rakel Tryggvadottir
    • , Tal H Salz
    •  & Andrew P Feinberg
  3. Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Tyler Saunders
    • , Alvin Makohon-Moore
    •  & Yi Zhong
  4. Duke Cancer Institute, Duke Molecular Physiology Institute, Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.

    • Samantha J Mentch
    • , Marc O Warmoes
    •  & Jason W Locasale
  5. Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

    • Alessandro Carrer
    •  & Kathryn E Wellen
  6. Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, USA.

    • Hao Wu
  7. Departments of Pathology and Human Oncology and Pathogenesis Program, David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Christine A Iacobuzio-Donahue
  8. Departments of Medicine, Biomedical Engineering and Mental Health, Johns Hopkins University Schools of Medicine, Engineering and Public Health, Baltimore, Maryland, USA.

    • Andrew P Feinberg


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O.G.M., C.A.I.-D., and A.P.F. conceived the work and wrote the manuscript. A.P.F. oversaw epigenomic sequencing performed at Johns Hopkins University. C.A.I.-D. selected patient samples, performed pathological review, analyzed immunostaining data, and oversaw whole-genome sequencing studies performed at MSKCC. O.G.M. designed and performed or oversaw all experiments and data analysis conducted at Vanderbilt. X.L. and H.W. performed the bioinformatic and statistical analyses. O.G.M. and A.P.F. guided the bioinformatic analyses. T.S. performed immunohistochemical and immunofluorescence experiments. R.T. prepared sequencing libraries and performed sequencing runs, assisted by T.H.S. S.J.M., M.O.W., and J.W.L. performed the LC–HRMS measurements of metabolites. O.G.M. and A.E.W. analyzed and plotted LC–HRMS data. A.C. and K.E.W. performed and analyzed YSI glucose and lactate measurements. S.N. and K.M.S. maintained cell culture and performed NADPH assays and a subset of immunoblotting. Y.Z. performed animal injection experiments. A.M.-M. performed whole-genome sequencing. O.G.M. prepared the figures. All authors approved the final version of the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Christine A Iacobuzio-Donahue or Andrew P Feinberg.

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    Data sets and correlation coefficients.

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    Supplementary Table 3

    Domain characteristics.

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    Supplementary Table 4

    Reprogramming within domains and sensitivity analyses.

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    Supplementary Table 7

    Gene expression changes.

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