Scientists have discovered new details about how pancreatic cancer constantly changes its genetic makeup, allowing it to become more aggressive, spread throughout the body and resist treatment. By examining nearly half a million individual cancer cells, researchers identified genetic changes that could reveal new ways to fight one of the deadliest forms of cancer.
The study, led by scientists at NYU Langone Health and its Perlmutter Cancer Center, focused on pancreatic ductal adenocarcinoma, a particularly difficult-to-treat cancer. Nearly 85 percent of patients die within five years of diagnosis.
Although researchers have already linked more than half a dozen genes to the disease, much is still unknown about how pancreatic cancer develops and adapts. By examining tumor cells individually rather than studying them in large groups, the team better understood how different populations of cancer cells change their DNA as the disease progresses.
How pancreatic cancer evolves to escape treatment
Researchers have discovered that pancreatic tumors contain a variety of distinct cell populations called clones. Each clone is made up of cancer cells with similar genetic characteristics, but their behavior can differ significantly.
Some clones develop changes that help them resist cancer treatments, while others become better equipped to invade surrounding tissues and spread to other parts of the body. These results suggest that the cancer’s ability to continually reorganize its genetic material plays a central role in treatment resistance and metastasis.
Previous studies generally divided pancreatic cancer cells into two main categories: classic (less aggressive) and basal (more aggressive). However, because these studies looked at large collections of cells together, scientists could not fully explain how cancer cells move from one category to another.
The latest findings help explain this process. Genetic changes occurring within individual tumors allow cancer cells to transition from one state to another, potentially making the disease more dangerous as it develops.
Scientists identify gene that could make pancreatic cancer less aggressive
Published on October 13 in Natural geneticsthe study identified several genetic changes associated with pancreatic cancer progression. One particularly important finding involved MYC, a gene that showed increased activity in some of the most aggressive cancer cell populations.
In other laboratory experiments, the researchers blocked MYC activity in aggressive basal pancreatic cancer cells. Remarkably, the cells returned to the less aggressive classical state.
The change also made cancer cells more exposed to immune cells, suggesting they may become easier to recognize and attack by the immune system. Although more research is needed, the results indicate that MYC is a promising target for future pancreatic cancer treatments.
“Our study provides the most granular view to date of pancreatic ductal adenocarcinoma, revealing how ongoing genetic remodeling drives tumor evolution over the course of disease,” said Despoina Kalfakakou, PhD, principal investigator of the study and postdoctoral scholar at NYU Grossman School of Medicine and the Perlmutter Cancer Center. “These results suggest that targeting mechanisms underlying tumor progression, including MYC, could help curb rapid cancer progression.”
“Our research also suggests that single-cell clonal analysis offers a better approach to understanding complex cancers, like pancreatic ductal adenocarcinoma, as they develop over time, mapping how tumors evolve and adapt at each stage of disease progression,” said study co-principal investigator Aristotelis Tsirigos, PhD, professor in the NYU Grossman Departments of Medicine and Pathology. School of Medicine and a member of the Perlmutter Cancer Center.
“More broadly, the results of our study highlight the critical role of clonal diversity, genetic plasticity, and interactions with the tumor microenvironment in shaping the biology of human pancreatic ductal adenocarcinoma,” said Dr. Tsirigos, also co-director of the Division of Precision Medicine and director of the Applied Bioinformatics Laboratories at NYU Langone.
Why pancreatic cancer can escape the immune system
The investigation also provided important clues about pancreatic cancer’s ability to hide from the immune system, a feature that could explain why the disease often responds poorly to immunotherapy.
Researchers found that some cancer cell clones had increased activity of the TIGIT gene, associated with proteins that help tumors evade immune detection.
At the same time, these clones showed reduced activity of the PD1 gene. This combination may help explain why immunotherapies designed to target PD1 have shown limited effectiveness against pancreatic cancer.
Understanding these differences between cancer cell populations could help scientists develop treatments that interfere with the specific mechanisms tumors use to avoid immune attacks.
According to Dr. Tsirigos, clinical trials of drugs that inhibit MYC or TIGIT are already underway for pancreatic ductal carcinoma and other cancers. He said the latest findings highlight the need for larger studies examining the different states cancer cells can adopt and how treatments could be tailored to target them.
Nearly half a million cancer cells reveal hidden tumor diversity
To study how pancreatic cancer changes over time, scientists examined gene activity (using transcriptomics) in 443,451 individual cells collected from 62 tumors belonging to 56 men and women diagnosed with pancreatic ductal adenocarcinoma.
Six of these patients also provided tumor samples before and after chemotherapy, allowing researchers to examine changes associated with treatment.
Unlike traditional approaches that measure changes in gene activity across large groups of cells, the new analysis looked at individual cells. This provided a much more detailed picture of the different populations of cancer cells living within the same tumor.
The results showed that individual tumors contained approximately two to 11 distinct clones, made up of various combinations of classical and basal cancer cells.
By tracing the genetic origins of these clones and comparing patterns of gene activity, the researchers linked differences in DNA copy numbers to the types of cells present in each tumor.
This approach allowed them to identify which genes, including MYC and TIGIT, were particularly active at different times during cancer progression.
Together, the findings provide insight into how pancreatic tumors grow, resist treatment and spread. They also suggest that interfering with the genetic mechanisms behind these changes could provide new opportunities to combat a disease that remains exceptionally difficult to treat.
Study funding and research team
The research was supported by National Institutes of Health Sky Foundation Grants P30CA016087 and R01CA245005.
In addition to Drs. Kalfakakou and Tsirigos, the NYU Langone research team included Daniel Cameron, MS; Emily Kawaler, Ph.D.; Ziaohong Jing, Ph.D.; Cristina H. Hajdu, MD; Dylan Tamayo, MS; Yoona Cale; Amanda Ackermann, MD, PhD; Daniel Weissinger; Rosmel Hernández, PhD; Matthew Beier, MD; Dacia Dimartino, PhD; Pierre Meyn; Kalina Rice, MS; Shanmugapriya Selvaraj, MS; Cynthia A. Loomis, MD, PhD; Adriana Héguy, Ph.D.; Amanda W. Lund, Ph.D.; and Igor Dolgalev, PhD.
Additional contributors from Oregon Health and Science University were co-investigators Motoyuki Tsuda, MD, PhD; Hayley Zimny; and Rosalie Sears, Ph.D.
Researchers from the University of California, San Diego included Lidong Wang, PhD; Qi Su, PhD; Sungsik Kim, Ph.D.; Hannah Carter, Ph.D.; Theodore Welling, MD; and Diane Simeone, MD, co-principal investigator of the study.
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