A new study from researchers at Johns Hopkins Medicine points to a potential mechanism through which normal pancreatic cells may adopt cancer-like traits, even in the absence of genetic mutations. The findings, published in Genome Medicine, suggest that inflammation-induced epigenetic changes can temporarily reprogram cells and leave behind a molecular “memory” that may set the stage for cancer.
Epigenetic marks were found in pancreatic acinar cells as they transitioned into a ductal-like state, a process known as acinar-to-ductal metaplasia. These transitional cells acquired epigenetic signatures commonly associated with pancreatic cancer, even though no cancer-driving mutations were present.
“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,” said Andrew Feinberg, Bloomberg Distinguished Professor at Johns Hopkins and co-lead author of the study.
Acinar cells, which produce digestive enzymes, can switch to a ductal-like identity in response to inflammation. This shift, while protective, appears to leave lasting epigenetic imprints. Using whole-genome sequencing of mouse pancreatic cells undergoing this transition, the team identified chemical modifications on genes associated with cancer, including members of the PI3K and R/R/C GTPase families, but did not detect changes in the DNA sequence itself.
These cells looked epigenetically similar to human pancreatic precancerous cells, called PanINs, that carry KRAS mutations, even though these mouse cells didn’t have the KRAS mutation. This suggests that a cancer-like state can be epigenetically imprinted before any mutations occur.
What stood out to the researchers was the persistence of these cancer-associated epigenetic marks. Even after the cells reverted back to their acinar identity, some of the modifications remained for at least seven days. This residual pattern points to a form of “epigenetic memory” that could prime cells for transformation under subsequent stress or mutation.
“This work shows a key role for epigenetic memory in the transition to cancer even without a genetic mutation,” Feinberg said.
“This transition state is probably a normal way that the pancreas protects itself from the corrosive impact of inflammation and other stressors,” added Patrick Cahan, Associate Professor of Biomedical Engineering at Johns Hopkins.
While the study focused on a mouse model, the parallels drawn with human pancreatic precancer suggest that transient epigenetic reprogramming could play a broader role in cancer risk, particularly in individuals without classical mutation profiles. The research adds to a growing body of evidence that epigenetic plasticity during cellular stress may have longer-term consequences than previously recognized.
Publication Details
Lo, E., Idrizi, A., Tryggvadottir, R. et al. DNA methylation memory of pancreatic acinar-ductal metaplasia transition state altering Kras-downstream PI3K and Rho GTPase signaling in the absence of Kras mutation. Genome Med 17, 32 (2025). https://doi.org/10.1186/s13073-025-01452-6
Epigenetic marks were found in pancreatic acinar cells as they transitioned into a ductal-like state, a process known as acinar-to-ductal metaplasia. These transitional cells acquired epigenetic signatures commonly associated with pancreatic cancer, even though no cancer-driving mutations were present.
“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,” said Andrew Feinberg, Bloomberg Distinguished Professor at Johns Hopkins and co-lead author of the study.
Acinar cells, which produce digestive enzymes, can switch to a ductal-like identity in response to inflammation. This shift, while protective, appears to leave lasting epigenetic imprints. Using whole-genome sequencing of mouse pancreatic cells undergoing this transition, the team identified chemical modifications on genes associated with cancer, including members of the PI3K and R/R/C GTPase families, but did not detect changes in the DNA sequence itself.
These cells looked epigenetically similar to human pancreatic precancerous cells, called PanINs, that carry KRAS mutations, even though these mouse cells didn’t have the KRAS mutation. This suggests that a cancer-like state can be epigenetically imprinted before any mutations occur.
What stood out to the researchers was the persistence of these cancer-associated epigenetic marks. Even after the cells reverted back to their acinar identity, some of the modifications remained for at least seven days. This residual pattern points to a form of “epigenetic memory” that could prime cells for transformation under subsequent stress or mutation.
“This work shows a key role for epigenetic memory in the transition to cancer even without a genetic mutation,” Feinberg said.
“This transition state is probably a normal way that the pancreas protects itself from the corrosive impact of inflammation and other stressors,” added Patrick Cahan, Associate Professor of Biomedical Engineering at Johns Hopkins.
While the study focused on a mouse model, the parallels drawn with human pancreatic precancer suggest that transient epigenetic reprogramming could play a broader role in cancer risk, particularly in individuals without classical mutation profiles. The research adds to a growing body of evidence that epigenetic plasticity during cellular stress may have longer-term consequences than previously recognized.
Publication Details
Lo, E., Idrizi, A., Tryggvadottir, R. et al. DNA methylation memory of pancreatic acinar-ductal metaplasia transition state altering Kras-downstream PI3K and Rho GTPase signaling in the absence of Kras mutation. Genome Med 17, 32 (2025). https://doi.org/10.1186/s13073-025-01452-6