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

Oliver G. McDonald, Xin Li, Tyler Saunders, Rakel Tryggvadottir, Samantha J. Mentch, Marc O. Warmoes, Anna E. Word, Alessandro Carrer, Tal H. Salz, Sonoko Natsume, Kimberly M. Stauffer, Alvin Makohon-Moore, Yi Zhong, Hao Wu, Kathryn E. Wellen, Jason W. Locasale, Christine A. Iacobuzio-Donahue, Andrew P. Feinberg

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)367-376
Number of pages10
JournalNature genetics
Volume49
Issue number3
DOIs
StatePublished - Mar 1 2017

ASJC Scopus subject areas

  • Genetics

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