Scientists have uncovered 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, conducted by scientists at NYU Langone Health and its Perlmutter Cancer Center, focused on pancreatic ductal adenocarcinoma, a particularly difficult cancer to treat. Nearly 85 percent of patients die within five years of being diagnosed.
Although researchers have already linked more than half a dozen genes to the disease, much remains unknown about how pancreatic cancer develops and adapts. By examining tumor cells individually rather than studying them in large groups, the team gained a clearer understanding of how different populations of cancer cells change their DNA as the disease progresses.
How Pancreatic Cancer Evolves To Escape Treatment
The researchers discovered that pancreatic tumors contain a variety of distinct cell populations known as clones. Each clone consists of cancer cells with similar genetic characteristics, but their behavior can differ dramatically.
Some clones develop changes that help them withstand cancer treatments, while others become better equipped to invade surrounding tissues and spread to other parts of the body. These findings suggest that the cancer’s ability to continually reorganize its genetic material plays a central role in both treatment resistance and metastasis.
Previous studies generally divided pancreatic cancer cells into two main categories: classical (less aggressive) and basal (more aggressive). However, because those studies examined large collections of cells together, scientists could not fully explain how cancer cells move from one category to the other.
The latest findings help explain this process. Genetic changes occurring within individual tumors allow cancer cells to shift between these two states, potentially making the disease more dangerous as it develops.
Scientists Identify a Gene That Could Make Pancreatic Cancer Less Aggressive
Published on October 13 in Nature Genetics, the study identified several genetic changes associated with pancreatic cancer progression. One particularly important finding involved MYC, a gene that showed heightened activity in some of the most aggressive cancer cell populations.
In additional laboratory experiments, the researchers blocked MYC activity in aggressive basal pancreatic cancer cells. Remarkably, the cells shifted back toward the less aggressive classical state.
The change also made the cancer cells more exposed to immune cells, suggesting they could become easier for the immune system to recognize and attack. Although further research is needed, the results point to MYC as 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 reshaping drives tumor evolution over the course of disease,” said study lead investigator Despoina Kalfakakou, PhD, a postdoctoral research fellow at NYU Grossman School of Medicine and Perlmutter Cancer Center. “These findings suggest that targeting the mechanisms underlying tumor evolution, including MYC, may help restrain the cancer’s rapid progression.”
“Our research also suggests that single-cell clonal analysis offers a better approach to understanding complex cancers, like pancreatic ductal adenocarcinoma, as it develops over time, by mapping how tumors evolve and adapt at each stage of disease progression,” said study co-senior investigator Aristotelis Tsirigos, PhD, a professor in the Departments of Medicine and Pathology at NYU Grossman School of Medicine and a member of Perlmutter Cancer Center.
“More broadly, our study results highlight the critical role of clonal diversity, genetic plasticity, and interactions with the tumor’s microenvironment in shaping human pancreatic ductal adenocarcinoma biology,” said Dr. Tsirigos, who is also co-director of the Division of Precision Medicine and director of NYU Langone’s Applied Bioinformatics Laboratories.
Why Pancreatic Cancer Can Evade the Immune System
The investigation also provided important clues about pancreatic cancer’s ability to hide from the immune system, a characteristic that may help explain why the disease often responds poorly to immunotherapy.
Researchers discovered that certain cancer cell clones showed increased activity of the TIGIT gene, which is associated with proteins that help tumors escape immune detection.
At the same time, these clones exhibited 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 attack.
According to Dr. Tsirigos, clinical trials investigating drugs that inhibit MYC or TIGIT are already underway for pancreatic ductal carcinoma and other cancers. He said the latest findings underscore the need for larger studies examining the different states cancer cells can adopt and how treatments might be tailored to target them.
Nearly Half a Million Cancer Cells Reveal Hidden Tumor Diversity
To investigate how pancreatic cancer changes over time, the 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 both 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 examined individual cells. This provided a much more detailed picture of the different cancer cell populations living within the same tumor.
The results showed that individual tumors contained approximately two to 11 distinct clones, consisting of varying combinations of classical and basal cancer cells.
By tracing the genetic origins of these clones and comparing patterns of gene activity, the researchers connected differences in DNA copy numbers with 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 points during cancer progression.
Together, the findings provide a more detailed understanding of how pancreatic tumors evolve, resist treatment, and spread. They also suggest that interfering with the genetic mechanisms driving these changes could offer new opportunities to combat a disease that remains exceptionally difficult to treat.
Study Funding and Research Team
The research was supported by the Sky Foundation and National Institutes of Health grants P30CA016087 and R01CA245005.
In addition to Drs. Kalfakakou and Tsirigos, the NYU Langone research team included Daniel Cameron, MS; Emily Kawaler, PhD; Ziaohong Jing, PhD; Cristina H. Hajdu, MD; Dylan Tamayo, MS; Yoona Shim; Amanda Ackermann, MD, PhD; Daniel Weissinger; Rosmel Hernandez, PhD; Matthew Beier, MD; Dacia Dimartino, PhD; Peter Meyn; Kalina Rice, MS; Shanmugapriya Selvaraj, MS; Cynthia A. Loomis, MD, PhD; Adriana Heguy, PhD; Amanda W. Lund, PhD; and Igor Dolgalev, PhD.
Additional contributors from Oregon Health and Science University were co-investigators Motoyuki Tsuda, MD, PhD; Hayley Zimny; and Rosalie Sears, PhD.
Researchers from the University of California San Diego included Lidong Wang, PhD; Qi Su, PhD; Sungsik Kim, PhD; Hannah Carter, PhD; Theodore Welling, MD; and co-senior study investigator Diane Simeone, MD.
