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.