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

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
Nat Genet. 2017 49 (3): 367-376

PMID: 28092686 · PMCID: PMC5695682 · DOI:10.1038/ng.3753

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.

MeSH Terms (12)

Carcinogenesis Carcinoma, Pancreatic Ductal Chromatin Epigenesis, Genetic Epigenomics Gene Expression Glucose Heterochromatin Histones Humans Neoplasm Metastasis Pancreatic Neoplasms

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