Pancreatic cancer is an often deadly disease that, even if successfully treated, has a relative survival rate of about 13%, according to the NIH. When detected and treated early, that survival rate increases substantially. Developing strategies to diagnose cancer early or identify precancerous tissues is vital to success and increased survival.
A common precursor to pancreatic cancer is the presence of lesions called pancreatic intraepithelial neoplasia (PanIN). Researchers from the University of Michigan and the University of Maryland have been studying these precursor lesions and previously identified metabolic biomarkers involved with the development of PanIN to cancer. In their new study, published in Cancer Discovery, they expand their work into the PanIN microenvironments—the cells and tissues directly surrounding the lesions—to understand the cellular changes in an effort to find markers to use in diagnostics.
To examine the microenvironments, the team utilized single-cell RNA sequencing and spatial transcriptomics, isolating single cells and mapping their gene expression.
“These lesions are like needles in a haystack,” said co-senior author Timothy Frankel, MD, professor of surgical oncology and co-director of the Rogel and Blondy Center for Pancreatic Cancer at the University of Michigan. “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.” He explained that using these precise techniques to examine cells individually is both more efficient and allows the researchers “to just focus in on the needle so we can look at multiple needles using the same amount of computing power and resources.”
The researchers used whole donated human pancreases to map the progression from PanIN to cancer, both for the precancerous and cancerous cells themselves, and the microenvironments surrounding them.
The pancreatic cancer microenvironment contains a highly diverse group of interactive cells, including fibroblasts and immune cells. The researchers found that while the epithelial tissue gene expression changes on a continuum from PanIN to cancer, the cells in the microenvironment are much more dynamic.
“Progression to cancer is accompanied by profound geographical reorganization of myeloid cells and lymphocytes and the formation of a cancer-specific fibroblast population characterized by high levels of Smooth Muscle Actin, LRRC15, and the WNT signaling component LEF1,” they wrote.
“It turns out, the microenvironment of these precursor lesions is the same as the microenvironment of the normal pancreas,” explained co-senior study author Marina Pasca di Magliano, PhD, professor of surgical immunology and co-director of the Rogel and Blondy Center for Pancreatic Cancer at the University of Michigan.
“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.”
These unexpected results indicate that there are other factors or stressors impacting the microenvironment. This is also in line with prior data showing that while pancreatic cancer is preempted by PanIN, not all, and in fact most, PanIN occurrences do not lead to a cancer diagnosis.
“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,” said co-corresponding author Elana J. Fertig, PhD, 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. “Through careful study design, we can use the spatial information to start delving into the unknown dynamics of pancreatic tumor evolution.”
Moving forward, more research is needed to identify those stressors that may impact the microenvironment surrounding PanINs, which would allow the lesions to turn into cancers. Understanding those switches may open the door for developing earlier diagnostics or therapies to help prevent cancer development in the first place.
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