title: Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis.
abstract: 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.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt-Ingram Cancer Center, and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Oliver G
authors.initials: OG
authors.lastname: McDonald
authors.affiliation: Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Saunders
authors.affiliation: Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Rakel
authors.initials: R
authors.lastname: Tryggvadottir
authors.affiliation: Duke Cancer Institute, Duke Molecular Physiology Institute, Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Mentch
authors.affiliation: Duke Cancer Institute, Duke Molecular Physiology Institute, Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Warmoes
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt-Ingram Cancer Center, and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Word
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Carrer
authors.affiliation: Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Tal H
authors.initials: TH
authors.lastname: Salz
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt-Ingram Cancer Center, and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Natsume
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt-Ingram Cancer Center, and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Stauffer
authors.affiliation: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Alvin
authors.initials: A
authors.lastname: Makohon-Moore
authors.affiliation: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Kathryn E
authors.identifier: http://orcid.org/0000-0002-2281-0042
authors.initials: KE
authors.lastname: Wellen
authors.affiliation: Duke Cancer Institute, Duke Molecular Physiology Institute, Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Jason W
authors.identifier: http://orcid.org/0000-0002-7766-3502
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: 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.
authors.forename: Christine A
authors.identifier: http://orcid.org/0000-0002-4672-3023
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Departments of Medicine, Biomedical Engineering and Mental Health, Johns Hopkins University Schools of Medicine, Engineering and Public Health, Baltimore, Maryland, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Feinberg
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D015870:Gene Expression / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D006570:Heterochromatin / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D009362:Neoplasm Metastasis / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D002843:Chromatin; D006570:Heterochromatin; D006657:Histones; D005947:Glucose