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Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis.

Publication ,  Journal Article
McDonald, OG; Li, X; Saunders, T; Tryggvadottir, R; Mentch, SJ; Warmoes, MO; Word, AE; Carrer, A; Salz, TH; Natsume, S; Stauffer, KM; Zhong, Y ...
Published in: Nat Genet
March 2017

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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Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

March 2017

Volume

49

Issue

3

Start / End Page

367 / 376

Location

United States

Related Subject Headings

  • Pancreatic Neoplasms
  • Neoplasm Metastasis
  • Humans
  • Histones
  • Heterochromatin
  • Glucose
  • Gene Expression
  • Epigenomics
  • Epigenesis, Genetic
  • Developmental Biology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
McDonald, O. G., Li, X., Saunders, T., Tryggvadottir, R., Mentch, S. J., Warmoes, M. O., … Feinberg, A. P. (2017). Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet, 49(3), 367–376. https://doi.org/10.1038/ng.3753
McDonald, Oliver G., Xin Li, Tyler Saunders, Rakel Tryggvadottir, Samantha J. Mentch, Marc O. Warmoes, Anna E. Word, et al. “Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis.Nat Genet 49, no. 3 (March 2017): 367–76. https://doi.org/10.1038/ng.3753.
McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, Warmoes MO, et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet. 2017 Mar;49(3):367–76.
McDonald, Oliver G., et al. “Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis.Nat Genet, vol. 49, no. 3, Mar. 2017, pp. 367–76. Pubmed, doi:10.1038/ng.3753.
McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, Warmoes MO, Word AE, Carrer A, Salz TH, Natsume S, Stauffer KM, Makohon-Moore A, Zhong Y, Wu H, Wellen KE, Locasale JW, Iacobuzio-Donahue CA, Feinberg AP. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet. 2017 Mar;49(3):367–376.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

March 2017

Volume

49

Issue

3

Start / End Page

367 / 376

Location

United States

Related Subject Headings

  • Pancreatic Neoplasms
  • Neoplasm Metastasis
  • Humans
  • Histones
  • Heterochromatin
  • Glucose
  • Gene Expression
  • Epigenomics
  • Epigenesis, Genetic
  • Developmental Biology