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

Abstract

During the evolutionary progression of pancreatic ductal adenocarcinoma (PDAC), heterogeneous subclonal populations emerge that drive primary tumor growth, regional spread, distant metastasis, and patient death1–3. However, the genetics of metastases largely reflects that of the primary tumor in untreated patients, and PDAC driver mutations are shared by all subclones1. This raises the possibility than an epigenetic process might operate during metastasis. Here we detected striking epigenetic reprogramming of global chromatin modifications during the natural evolutionary history of distant metastasis. Genome-wide mapping revealed that global changes were targeted to thousands of large chromatin domains across the genome that collectively specified malignant traits, including euchromatin and large organized chromatin K9-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 malignant chromatin and expression states and blocked tumorigenicity. This suggests a model whereby linked metabolic-epigenetic programs are selected for enhanced tumorigenic fitness during the evolution of distant metastasis.

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

“…This mechanism appears to be distinct from our observations in PDA, since we did not observe generalized increases in chromatin accessibility associated with metastasis in this setting. Disruption of large heterochromatin domains of H3K9/H4K20 methylation has also recently been linked with PDA metastasis (McDonald et al, 2017). Within this larger body of evidence of epigenetic deregulation in metastasis, our study calls attention to alterations of the enhancer landscape as a mechanism by which tumor cells gain metastatic potential.…”

“…In addition, small-molecules that target readers, writers, or erasers of histone modifications have shown promising therapeutic effects in mouse models of PDA by altering transcription of cancer genes (Hessmann et al, 2017). A recent study has shown that disruption of large heterochromatin domains is associated with the metastatic transition in PDA, as a consequence of aberrant oxidative pentose phosphate metabolism (McDonald et al, 2017). However, the direct functional evidence that links chromatin regulation to PDA metastasis remains limited.…”

The impact of cellular metabolism on chromatin dynamics and epigenetics

“…This study indicated that LKB1-deficiency could be a key vulnerability as DNA methyltransferase and serine metabolism inhibition reduced tumor growth 117 . A distinct line of work on the evolution of distant metastases of pancreatic ductal adenocarcinoma (PDAC) demonstrated that the oxidative branch of the pentose phosphate pathway (oxPPP) was a driving force for epigenome landscape reprogramming and the fitness of metastatic cells 118 , suggesting that targeting the oxPPP could be effective in metastatic PDAC. Together, these studies represent a few examples on how advances in our understanding of metabolic effects on epigenetics can be translated into potential therapies.…”

Tumor Heterogeneity in Pancreatic Adenocarcinoma

“…While their genomic landscape is very similar, it has appears that they had very different epigenomic reprogramming [52]. Depending on the localization, the distribution of the different histone types and modifications varies and this results in a wide modification of Phylogenetic tree illustrating the tumor evolution and intratumor heterogeneity in pancreatic adenocarcinomas (adapted from Makohon-Moore et al [47]).…”