In a breakthrough that deepens our understanding of cancer’s earliest whispers, Johns Hopkins Medicine scientists have identified a distinctive pattern of epigenetic modifications in mouse pancreatic cells as they transition from a healthy to a precancerous state. Crucially, these “marks” appear to leave a lingering cellular memory—even after cells revert to normal—hinting at a hidden software-like layer of cancer risk.

“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 at Johns Hopkins University.

Unlike genetic mutations, which rewrite the DNA hardware, epigenetic marks function more like software: chemical tags that switch genes on or off without altering the underlying sequence. Feinberg and his colleagues, funded by the National Institutes of Health, published their findings March 28 in Genome Medicine, spotlighting how inflammation-induced stress can rewrite this cellular software in ways that nudge cells toward malignancy.

When the pancreas is inflamed—a hallmark of conditions like pancreatitis—its acinar cells (enzyme factories) morph into ductal-like cells, ostensibly to shield themselves from damage. This process, known as acinar-to-ductal metaplasia (ADM), has long been observed, but the epigenetic underpinnings remained elusive.

“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,” Feinberg explained.

To probe this, Feinberg and co-lead Patrick Cahan, Ph.D., sequenced the entire genome of mouse pancreatic cells undergoing ADM. They focused on two groups of genes—PI3K and R/R/C GTPase—that have been linked to early stages of human pancreatic cancer caused by KRAS mutations. Remarkably, although the mice lacked such mutations, their transitioning cells bore the same epigenetic signatures.

“This suggested that the transitioning cells took on epigenetic characteristics of precancerous cells without requiring a mutation and inched closer to becoming cancer," Feinberg notes.

Perhaps the most striking discovery was the persistence of these marks. After the hybrid cells reverted to their original acinar identity, a subset of cancer-linked epigenetic modifications lingered for at least seven days—a molecular “memory” of stress-induced change.

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

Cahan underscores the physiological rationale behind ADM, saying, “This transition state is probably a normal way that the pancreas protects itself from the corrosive impact of inflammation and other stressors.”

Yet, in protecting itself, the organ may inadvertently record a memory of its distress—one that could prime cells for future malignant transformation.

Feinberg speculates that such epigenetic memories may shed light on an unsettling trend: the rise of cancers in younger populations who haven’t accumulated many age-related genetic mutations. If inflammation and environmental stressors etch precancerous marks into cellular software, they may accelerate the timeline from healthy cell to malignancy.

“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.” Feinberg suggests.

The findings of the Johns Hopkins team not only underscore the intricate ballet between inflammation and cancer risk but also open avenues for early detection. By identifying and potentially erasing maladaptive epigenetic marks, researchers may one day intercept cancer’s earliest steps—rewriting the software before the hardware is damaged.