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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • March 2017

Published In

Volume / Issue

  • 49 / 3

Start / End Page

  • 367 - 376

PubMed ID

  • 28092686

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

International Standard Serial Number (ISSN)

  • 1061-4036

Digital Object Identifier (DOI)

  • 10.1038/ng.3753

Language

  • eng