Studying a Forerunner of Pancreatic Cancer Reveals New Clues about How the Disease Develops

Pancreatic tumor cells

Researchers are studying the genetic changes that occur early in the development of a pancreatic tumor, like that shown above. Source: CNRI/Science Source.

One universal truth about cancer is that the later it’s detected, the harder it is to treat. Pancreatic cancer is one form of the disease that is almost always found when it’s advanced, making it an exceptional challenge. Because it’s rarely caught early in its development, this also means that researchers know less about what drives its formation and spread than they do with many other kinds of tumors.

Understanding how a cancer develops and grows, however, has important implications. It allows researchers to create better targeted therapies and develop better detection and screening methods. Now a study led by Memorial Sloan Kettering physician-scientist Christine Iacobuzio-Donahue is shedding new light on a phenomenon that sometimes leads to pancreatic cancer. The results were published September 3, 2018, in Nature.

A Possible Lead-Up to Cancer

When surgeons remove a cancerous pancreas, they often find groups of abnormal cells called pancreatic intraepithelial neoplasias (PanINs) in other parts of the organ. PanINs are also common in older people who do not have pancreatic cancer.

Pancreatic intraepithelial neoplasias are common in older people and don’t always turn into pancreatic cancer.

Although they are not cancer, some PanINs eventually become cancer. Experts aren’t sure how often that happens. “I think of them sort of like moles on the skin,” says first author Alvin Makohon-Moore. “It may not turn into anything serious, but it’s clear that some sort of change has taken place that could further transform into cancer.” Dr. Makohon-Moore is a postdoctoral fellow in Dr. Iacobuzio-Donahue’s lab.

In the new study, the investigators identified eight people who had undergone surgery for early-stage pancreatic cancer who also had PanINs in other parts of their pancreas. The patients were treated at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, where Dr. Iacobuzio-Donahue and her colleagues worked when this research began. Several investigators from Johns Hopkins also contributed to the Nature paper.

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The Search for Genetic Similarities — and Differences

The pancreas tissue was dissected under a microscope, and the cells from each PanIN were separated from the tumor cells in a very precise way. The DNA from each PanIN was then extracted, and the researchers conducted whole exome sequencing. This involves sequencing all the sections of the genome that are known to encode proteins. The tumors were also sequenced. For both types of cells, the investigators sorted out which mutations were likely to be directing cancer growth (called driver mutations) and which were just along for the ride (called passenger mutations).

“The goal of this research was to find mutations that the tumors and PanINs had in common and other mutations that the PanINs and tumors had acquired independently,” Dr. Makohon-Moore explains. “Based on this, we could create evolutionary trees for each patient, to figure out how their tumors had evolved.”

Eventually, we hope this research will give us a framework for interpreting the events that happen early in the development of pancreas tumors.
Alvin Makohon-Moore researcher

Based on the driver mutations found in the PanINs and tumors, the team was able to determine which cancer-causing mutations led to invasive cancer and which were acquired later. Unexpectedly, they also found that the PanINs could move through the system of ducts in the pancreas.

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Potential for Further Research

There are several important next steps in the research. One is to look at a greater number of PanINs and tumors to determine if there are any repeated genetic patterns. That’s difficult to do with samples from only eight people.

Another step is to look for attributes beyond the DNA that may be driving the formation of tumors. This will include studies of the cells around the PanINs. This area is called the microenvironment. Researchers will also look for changes in gene expression that are not reflected in the DNA sequence — called epigenetic changes.

“Eventually, we hope this research will give us a framework for interpreting the events that happen early in the development of pancreas tumors,” Dr. Makohon-Moore says.

He adds that this inquiry may provide an explanation for why pancreatic cancer comes back so often after surgery. Even for people with early-stage disease whose tumors are completely removed, the disease returns in 60 to 70% of them. “It could be that these tumors are not as localized as we think they are and that they have the ability to move around within the pancreas,” he says. “Our research may help provide a biological context for why this cancer is so aggressive.”

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