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New Insights into Pancreatic Cancer Development
Researchers at Johns Hopkins Medicine have identified a significant pattern of epigenetic “marks” during the transition from normal pancreatic cells to cancerous cells in a mouse model, suggesting that normal pancreatic cells may retain a temporary “memory” of alterations associated with cancer.
Epigenetic marks refer to chemical modifications that regulate gene expression without modifying the underlying DNA sequence. This process can be likened to software programming in a computer, where epigenetics overlays essential instructions that direct how genetic information is used.
This groundbreaking study, which received funding from the National Institutes of Health, was published online on March 28 in the journal Genome Medicine. The findings pave the way for a deeper understanding of the processes involved when normal cells transform into cancerous cells, highlighting the influence of inflammation and cellular damage in this complex transformation.
“Research into epigenetic alterations has been crucial in explaining how cells transition from their normal state to cancer,” noted Andrew Feinberg, M.D., Bloomberg Distinguished Professor across the schools of medicine, engineering, and public health at Johns Hopkins University.
He elaborated, stating, “This transition is initiated when cells develop an altered identity due to inflammation or damage, which may predispose them to cancerous changes even in the absence of the mutations typically thought to drive cancer.”
Previous understanding indicated that when the pancreas is inflamed, acinar cells—responsible for producing digestive enzymes—begin a transformation into ductal cells, which help transport digestive juices. This adaptation is believed to enable acinar cells to better safeguard themselves from damage stemming from inflammation.
Given the epigenome’s role in regulating gene expression and defining cellular identity, Feinberg emphasized its importance in studying the conversion of acinar cells as they undergo transformation.
Co-led by Feinberg and Patrick Cahan, Ph.D., an associate professor of biomedical engineering, the study focused on analyzing the transitioning pancreatic cells in mice, whose characteristics are similar to those in humans. The research team, which included first author Emily Lo, conducted whole-genome sequencing of pancreatic cells undergoing acinar-to-ductal metaplasia.
The findings revealed the presence of epigenetic markers on genes associated with pancreatic cancer, including two gene groups known as PI3K and R/R/C GTPase, without any mutations in the actual DNA sequence. Previous work had indicated that similar epigenetic changes occur in human precancerous pancreatic lesions, known as PanINs, which result from mutations in the KRAS gene. This observation suggests that the transitioning cells could acquire precancerous epigenetic characteristics independent of mutations, edging them closer to cancer development, according to Feinberg.
Notably, researchers observed that when the cells reverted to their original acinar state, some epigenetic marks on cancer-related genes persisted for at least seven additional days, indicating a form of epigenetic “memory.” Feinberg stated, “This research emphasizes the crucial role of epigenetic memory in the onset of cancer, even in the absence of genetic mutations.”
Cahan added, “Such transition states may represent a natural mechanism through which the pancreas shields itself from the damaging effects of inflammation and other stressors.”
Feinberg suggests that further investigations could uncover how these transition-related epigenetic changes might explain the observed rise in cancer cases among younger populations, who may not yet have accumulated the usual age-related mutations in their DNA.
Additional contributors to this research from Johns Hopkins include Adrian Idrizi, Rakel Tryggvadottir, Weiqiang Zhou, Wenpin Hou, and Hongkai Ji. The research was financially supported by various grants from the National Institutes of Health (CA054358, 5F31CA250489, K99HG011468).
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