Pancreatic cells ‘remember’ epigenetic precancerous marks without genetic sequence mutations

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Johns Hopkins Medicine scientists say they have found a pattern of so-called epigenetic “marks” in a transition state between normal and pancreatic cancer cells in mice, and that the normal cells may keep at least a temporary “memory” of those cancer-linked marks. 

Epigenetic marks are chemical modifications that help regulate genetic expression without directly altering DNA sequence in the makeup of genes. While the genetic code is like a computer’s hardware, epigenetics involves chemical marks on top of the genetic code that act as software programing in a computer. 

The new research, funded by the National Institutes of Health and published online March 28 in the journal Genome Medicine, supports efforts to better understand how normal cells morph into cancer, along with the roles of inflammation and cellular damage in that process. 

“Epigenetic changes have long been a focus of research seeking to explain how cells transition from normal to cancer,” says Andrew Feinberg, M.D., Bloomberg Distinguished Professor in the Johns Hopkins University schools of medicine, engineering and public health. 

“The transition begins when cells acquire an altered or hybrid identity, because of inflammation or damage, that can potentially predispose them to a cancerous state, even without cancer-driving mutations,” he says. 

Scientists have known that, when the pancreas becomes inflamed, acinar cells, which produce digestive enzymes, begin to transform into ductal cells, which transport digestive juices in the pancreas. This transformation helps acinar cells protect themselves from damage caused by the inflammation. 

Because the epigenome decides which genes are turned on and off to give cells their identity, its role in the transformation of acinar cells warranted study, Feinberg says. 

Feinberg, who co-led the new study with Patrick Cahan, Ph.D., associate professor of biomedical engineering at Johns Hopkins, therefore took a closer look at the transforming or hybrid pancreatic cells in mice, which the scientists say, have characteristics similar to human pancreatic cells. 

The scientists, including first author Emily Lo, who was co-mentored by Cahan and Feinberg, did so by sequencing the whole genome of mouse pancreatic cells transitioning between acinar and ductal cells, in a process called acinar-to-ductal metaplasia. They found epigenetic marks, but no mutations (alterations in the DNA sequence itself), on genes linked with pancreatic cancer, including two groups called PI3K and R/R/C GTPase. They had earlier shown the same type of epigenetic changes in these genes in human pancreatic precancers termed PanINs, which are caused by a mutation in a gene called KRAS, even though there was no such mutation in the mouse cells. This suggested that the transitioning cells took on epigenetic characteristics of precancerous cells without requiring a mutation, and inch closer to becoming cancer, says Feinberg. 

When the transitioning cells returned to their original identity as acinar cells, the scientists found that some of the epigenetic marks on pancreatic cancer-linked genes remained for at least seven more days, forming a “memory” of the epigenetic signature. 

“This work shows a key role for epigenetic memory in the transition to cancer even without a genetic mutation,” says Feinberg. 

"This transition state is probably a normal way that the pancreas protects itself from the corrosive impact of inflammation and other stressors," says Cahan. 

Feinberg speculates that further studies may reveal that the epigenetic changes happening in a cell’s transition state may explain the increasing frequency of cancer in young people, since they may not have acquired age-associated mutations to the genetic code itself. 

Additional Johns Hopkins researchers who contributed to the study include Adrian Idrizi, Rakel Tryggvadottir, Weiqiang Zhou, Wenpin Hou and Hongkai Ji. 

Funding for the research was provided by the National Institutes of Health (CA054358, 5F31CA250489, K99HG011468).

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