Immunofluorescence image of human donor pancreas with a precursor lesion lined by epithelial cells surrounded by fibroblasts. Credit: Pasca Lab

In an unexpected finding, a new study flips on its head researchers’ understanding of how precancerous pancreas lesions evolve into pancreatic cancer. The paradigm-changing discovery has tremendous implications for identifying people at higher risk of cancer or even, potentially stopping malignant transformation. In tumors, cancer cells induce surrounding non-malignant cells to become “helpers” and promote tumor growth. This is called the microenvironment.

Precursor lesions called pancreatic intraepithelial neoplasia, or PanIN, similarly are surrounded by a collective of other cells. The precursor lesions express a similar set of genes as cancer cells but less strongly. So when researchers looked at the cells in the environment surrounding the lesions, they expected to see the same “tumor light” features. Surprisingly, the microenvironment of the precursor lesions was entirely different.

“It turns out, the microenvironment of these precursor lesions is the same as the microenvironment of the normal pancreas. The lesions have not convinced any of the cells around them to change. That’s not what we were expecting. We were expecting the two components, the cells and the microenvironment, to evolve in lockstep. They did not,” said co-senior study author Marina Pasca di Magliano, Ph.D., Maud T. Lane Professor of Surgical Immunology and Co-director of the Rogel and Blondy Center for Pancreatic Cancer at the University of Michigan.

The study is published in Cancer Discovery, a journal of the American Association for Cancer Research.

This discovery likely explains earlier research from the team that showed precursor lesions are common, including in younger people, while pancreatic cancer remains relatively rare. The transformation of normal pancreas cells into pancreatic cancer has been challenging to study in humans. Microscopic precursor lesions are extremely difficult to isolate in the pancreas and have typically been recovered during surgery when a nearby tumor is removed.

At this point, the PanIN microenvironment is likely influenced by the nearby tumor. The team benefited from a unique collaboration between the U-M Rogel Cancer Center and Gift of Life Michigan, which allows U-M researchers to procure healthy donor pancreases for research. From this partnership, researchers have isolated PanIN lesions from more than 150 donated pancreases from individuals ages 20-70.

For this study, they used multiple cutting edge research technologies, including single cell RNA sequencing and spatial transcriptomics, to isolate single cells, examine them in two dimensions and map the gene expression of specific tissue sections.

“These lesions are like needles in a haystack. The prior way of looking at this was to look at the entire haystack. You get a lot of information about hay and very little information about the needle. These new techniques allow us to just focus in on the needle so we can look at multiple needles using the same amount of computing power and resources,” said co-senior author Timothy Frankel, M.D., Maud T. Lane Professor of Surgical Oncology and co-director of the Rogel and Blondy Center for Pancreatic Cancer at U-M.

Pancreatic cancer has an extensive tumor microenvironment, which includes fibroblasts and immune cells that play complex roles in the biology of the tumor. If precursor lesions are not surrounded by that same microenvironment, it suggests that something else needs to happen to trigger cancer growth – inflammation, pancreatitis, smoking, age, obesity or other stressors linked to pancreatic cancer.

Future studies will seek to understand what factors are involved. The hope is that if researchers can understand how those stressors impact the microenvironment and allow precancerous lesions to turn into cancer, they can target cells involved in that process, intercept them and potentially stop the conversion.

The study reflects the critical role of multidisciplinary team science in pancreatic cancer research. In this case, the robust team at U-M’s Rogel and Blondy Center for Pancreatic Cancer leveraged its unique relationship with Gift of Life and their expertise in pancreatic cancer and its microenvironment, then partnered with additional experts in bioinformatics and pathology at the University of Maryland School of Medicine and New York University.

“It is incredible to see how we can uncover the fundamental cellular mechanisms of disease etiology by blending new computational methods and cutting-edge spatial transcriptomics technologies. Through careful study design, we can use the spatial information to start delving into the unknown dynamics of pancreatic tumor evolution,” said co-corresponding author Elana J. Fertig, Ph.D., Director of the Institute for Genome Sciences at the University of Maryland School of Medicine and Associate Director of Quantitative Sciences at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center.

To foster further discovery, the authors have created an open access website and interactive tool to allow other researchers to query the data.

Source – Michigan Medicine