An unexpected discovery leads a new study to upend the lead researcher’s understanding of how precancerous pancreatic lesions develop into pancreatic cancer. This paradigm-changing discovery has profound implications for identifying people at high risk of cancer and even stopping malignant metastasis.
In tumors, cancer cells induce surrounding non-malignant cells to act as “helpers” and promote tumor growth. This is called the microenvironment. A precursor lesion called a pancreatic intraepithelial neoplasia (PanIN) is similarly surrounded by a collection of other cells.
Precursor lesions express a similar set of genes as cancer cells, but not as strongly. So when the researchers looked at cells in the environment around the lesion, they expected to see the same “tumor light” signature. Remarkably, the microenvironment of the precursor lesions was quite different.
The microenvironment of these precursor lesions was found to be similar to that of the normal pancreas. I am not convinced that the lesion changes the surrounding cells. It wasn’t what we expected. We expected that the two components, cells and microenvironment, would evolve in tandem. they didn’t. ”
Dr. Marina Pasca Di Mariano, co-senior study author, Maude T. Lane Professor of Surgical Immunology, and co-director of the University of Michigan Rogel Blondie Pancreatic Cancer Center
This research cancer discoveryJournal of the American Association for Cancer Research;
This finding may explain previous research by the team that showed that while pancreatic cancer remains relatively rare, precursor lesions are common, including in younger people.
It has been difficult to study the transformation of normal pancreatic cells into pancreatic cancer in humans. Microscopic precursor lesions are very difficult to isolate within the pancreas and usually resolve when nearby tumors are removed during surgery. At this point, the PanIN microenvironment may be influenced by nearby tumors.
The research team benefited from a unique collaboration with UM Rogel Cancer Center and Gift of Life Michigan. This allows UM researchers to obtain healthy donor pancreases for research. Through this partnership, researchers isolated PanIN lesions from more than 150 donated pancreases from individuals aged 20 to 70 years.
In this study, we used multiple cutting-edge research techniques, including single-cell RNA-seq and spatial transcriptomics, to isolate single cells, examine them in two dimensions, and map gene expression in specific tissue sections.
“These lesions are like needles in a haystack. The previous way to look at this was to look at the whole haystack. You get a lot of information about the hay, but very little about the needles. With these new technologies, we can find the needles. “We can examine multiple needles using the same amount of computing power and resources,” said co-senior author Timothy Frankel, MD, Maud T. Lane Professor of Surgical Oncology and co-director. of UM’s Rogel and Blondie Pancreatic Cancer Center.
Pancreatic cancer has an extensive tumor microenvironment that includes fibroblasts and immune cells that play complex roles in tumor biology. If the precursor lesions are not surrounded by the same microenvironment, it suggests that something else needs to happen to trigger cancer growth, such as inflammation, pancreatitis, smoking, aging, obesity, or other stressors associated with pancreatic cancer. Future research will need to understand what factors are involved.
The hope is that if researchers can understand how these stressors affect the microenvironment and cause precancerous lesions to turn into cancer, they may be able to target and interrupt the cells involved in the process and halt the transformation.
This study reflects the important role of interdisciplinary team science in pancreatic cancer research. In this case, the strong team at UM’s Rogel and Blondie Pancreatic Cancer Centers leveraged their unique relationship with Gift of Life, their expertise in pancreatic cancer and its microenvironment, and partnered with additional experts in bioinformatics and pathology at the University of Maryland School of Medicine and New York University.
“It’s incredible to see how the fusion of new computational methods and state-of-the-art spatial transcriptomics techniques can reveal fundamental cellular mechanisms of disease pathogenesis. Through careful study design, we can use spatial information to begin to delve into the unknown dynamics of pancreatic tumor evolution,” said co-corresponding author Elana J. Fertig, Ph.D., director of the University of Maryland School of Medicine’s Genome Sciences Institute and director of the Institute for Genome Sciences. in Quantitative Science from the University of Maryland Marine College and the Stewart Greenbaum Comprehensive Cancer Center.
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Michigan Medicine – University of Michigan
Reference magazines:
El Hossini, A.M. others. (2026). Asynchronous evolution of epithelium and stroma distinguishes precursor lesions from pancreatic cancer. cancer discovery. https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-25-2001/785296/Asynchronous-evolution-of-epithelium-and-stroma
