An Epigenetic Signature Reveals the Cellular Origin of Pancreatic Cancer

Pancreatic cancer is one of the deadliest forms of cancer, in part because tumors can differ greatly from one patient to another. This study shows that some of this diversity may be explained by the type of pancreatic cell from which the tumor originates. The researchers developed an epigenetic “signature” based on DNA methylation patterns that can reveal whether a tumor arose from enzyme-producing acinar cells or from ductal cells that form the pancreatic duct network. By providing a way to identify the cellular origin of pancreatic tumors, this discovery could explain why some pancreatic cancers behave differently and respond differently to treatment. It also improves the use of experimental models of pancreatic cancer by allowing researchers to better characterize the tumors they study. In the longer term, this approach could support the development of more personalized treatment strategies, helping clinicians tailor therapies according to the cellular origin of each patient’s cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, characterized by high cellular and molecular diversity. Understanding the origin of this heterogeneity is essential for better treating this cancer. The cell that gives rise to a tumor (the cell of origin) is considered one of the factors contributing to this heterogeneity, as it may influence the behavior of PDAC and its response to treatment. In PDAC, tumors can originate from either pancreatic acinar or ductal cells which in a healthy pancreas produce digestive enzymes, or form the network of pancreatic ducts, respectively. Yet, despite the importance of the cell of origin for tumor biology, there is currently no established method to identify the cellular origin of a given PDAC.

The KPC mouse model, the most widely used model of PDAC in basic and translational research, reproduces many features of human pancreatic cancer. However, because oncogenic mutations are introduced early during pancreatic development, it remained unclear whether KPC tumors originate from acinar or ductal cells.Using DNA methylation profiling, Illiana Zoi, Patrick Jacquemin and their collaborators developed a new epigenetic approach to identify the cellular origin of mouse pancreatic tumors. They discovered a specific DNA methylation signature that distinguishes acinar-derived from ductal-derived PDAC cells and demonstrated that this signature is preserved during cancer development. Applying this signature to KPC-derived tumor cell lines revealed that these tumors can arise from acinar or ductal cells, providing a new explanation for pancreatic cancer heterogeneity.

This work has important implications for translational studies using the KPC model, as tumors from KPC mice included in a same study, as well as PDAC cell lines derived from these tumors, can differ in their cellular origin. Such differences could influence experimental outcomes, including drug sensitivity, thus introducing a source of variability and affecting study conclusions. The DNA methylation-based signature provides a tool to determine the cell of origin of KPC tumors and cell lines. Its use should help ensure that experimental groups are comparable with respect to their cellular origin, thereby increasing translational relevance of studies performed with this widely used PDAC model. In the future, a similar epigenetic signature could help stratify human PDAC according to their cellular origin, paving the way toward more precise disease modeling and personalized therapeutic strategies.

Article describing this research

DNA methylation-based classification uncovers acinar and ductal origins for KPC-derived PDAC cell lines

Zoi I, Rajput M, Holguín-Horcajo A, Haidar M, Brusa D, Chu K, Xie J, Shields M, Morgadinho Ferreira S, Stanger B, Attardi LD, Kopp J, Stemmler MP, Nicolle R, Rovira M, Jacquemin P

Cancer Letters (2026) 656:218666