Epigenomic Changes Prime PDAC Metastasis

Scientists at the Johns Hopkins Center for Epigenetics in Baltimore, MD, have uncovered evidence that widespread chromatin modifications and DNA methylation could be responsible for inducing the spread of pancreatic ductal adenocarcinoma (PDAC) cells to distant sites. Their findings also indicate a key role for glucose metabolism, through the oxidative pentose phosphate pathway (oxPPP), in priming metastasis.

“We set out to determine whether or not there were epigenomic drivers of pancreatic cancer progression,” says Andrew Feinberg, MD, MPH, the study's co–senior author. “The answer, in short, is yes.”

Feinberg and his team generated 160 datasets using primary, local (peritoneal), and distant (liver, lung) metastatic tumor samples from eight patients. The data were then analyzed for DNA methylation changes and modifications to transcriptionally active euchromatin as well as heterochromatin, which is generally inactive. The researchers reported that, compared with PDAC that had spread locally, distant metastases exhibited a large-scale loss of DNA methylation. Recurrent modifications of specific histones were also observed in the latter, including increased acetylation of H3K27 in euchromatin domains, and reduced dimethylation of H3K9 across large blocks of heterochromatin called LOCKs.

These widespread epigenomic variations in turn influenced the expression of various genes, ultimately conferring survival and growth advantages to metastasis-prone PDAC cells, Feinberg notes. For instance, closely examining one patient's distant metastatic subclone, the team found that DNA-repair genes were upregulated, and genes involved in KRAS–ERK signaling were downregulated. As such, this particular subclone was highly resistant to both chemotherapy and ERK inhibition.

Observing excessive glucose consumption in distant PDAC metastases, the researchers then went on to discover that these tumor cells rely on oxPPP—a metabolic pathway parallel to glycolysis—for their sugar needs. By knocking down a key enzyme in this pathway, PGD, or inhibiting it with an experimental agent called 6AN, “we partially reversed the epigenomic changes seen in these tumors,” Feinberg says. “It looks like these changes are metabolically coupled. In several laboratory assays, 6AN also selectively and strongly blocked tumor formation by cells from distant metastatic subclones.”

Eileen O'Reilly, MD, associate director for pancreatic cancer research at Memorial Sloan Kettering Cancer Center in New York, NY, thinks this study “provides thoughtful, provocative insights—independent of more conventional driver mutation explanations—about the metastatic process of PDAC.” The findings imply that developing therapies that target metabolism or result in epigenomic-level modulation may have value, but “both fields are still in their infancy” as far as this disease is concerned, O'Reilly notes, so further preclinical assessments of such strategies are warranted.

To Feinberg, these observations in PDAC fit an idea he and several colleagues have long held about cancer in general—that “stochastic epigenomic changes are a major driving force for tumor evolution, allowing rapid selection for growth-favoring tumor traits in a changing microenvironment.”

“I think the overall message here is hopeful,” he adds, “because what we've found suggests these epigenomically driven steps in pancreatic cancer progression are potentially reversible.” –Alissa Poh