Pancreatic Cancer Cells Constantly Rewrite Their DNA to Outsmart Treatment

Pancreatic cancer remains one of the most formidable opponents in modern oncology, and a new study has revealed exactly why it is so difficult to defeat. Researchers at NYU Langone Health and its Perlmutter Cancer Center have produced the most detailed picture to date of pancreatic ductal adenocarcinoma, the aggressive cancer that kills nearly 85 percent of patients within five years of diagnosis. By analyzing nearly half a million individual cells taken from dozens of patient tumors, the team showed that cancer cells are not static targets but constantly shifting populations that rewrite their genetic makeup over time, allowing them to slip past therapies and spread through the body.

The study, published online Oct. 13 in the journal Nature Genetics, examined the genetic activity of 443,451 single cells drawn from 62 tumors in 56 men and women with pancreatic ductal adenocarcinoma. Six of those patients provided tumor samples both before and after chemotherapy, giving the researchers a rare before-and-after window into how the disease responds to treatment pressure. Traditionally, tumor cells have been analyzed in bulk, measuring average upticks and decreases in gene activity across large groups of cells. That approach, the researchers argue, masks the critical differences between individual cells and the subpopulations they form.

By contrast, the single-cell approach allowed the team to identify distinct clones within each tumor — clusters of cells that share a similar genetic makeup. Rather than finding a uniform population of cancer cells, the researchers discovered that individual tumors contained on average between two and 11 different mixes of basal and classical tumor cells, the two major subtypes of pancreatic ductal adenocarcinoma. Classical cells are generally considered less aggressive, while basal cells are associated with a more virulent form of the disease. The striking diversity within a single tumor helps explain why treatments that appear to work against one population of cells may leave others untouched.

Perhaps the most consequential finding is that these clones behave in dramatically different ways. Some evolved to resist therapy, while others acquired the ability to spread rapidly to new sites in the body. When the researchers traced the clones’ genetic origins based on gene activity, they were able to link cell copy variations — changes in the number of copies of particular genetic regions — to the cellular composition of tumors. This mapping revealed which genes, such as MYC and TIGIT, were most active at different stages of disease progression, offering a dynamic view of tumor evolution rather than a single frozen snapshot.

Past research analyzing bulk groups of pancreatic cancer cells had separated the disease into the classical and basal subtypes, but it could not explain how cancer cells shift between them. The new findings show that genetic reconfiguration within a tumor enables cells to transition between these states. In other words, a tumor is not simply a mixture of two fixed cell types; it is a shifting ecosystem in which cells can change identity as the disease progresses. This plasticity, the researchers suggest, is a central engine driving both treatment resistance and metastasis in pancreatic cancer.

Among the specific genetic changes that emerged during tumor evolution, the team identified increased activity of the MYC gene in the most aggressive tumor cell populations. MYC is a well-known driver of cell growth and proliferation, and its heightened activity in basal-like populations marks it as a potential vulnerability. In further experiments with pancreatic basal tumor cells, the researchers found that blocking MYC activity reverted the cells to the less aggressive classical form. Remarkably, this shift also exposed the cells to more immune cells, potentially making them more vulnerable to immune attack — a double benefit that could make future therapies more effective.

The study also shed light on one of the most frustrating mysteries in pancreatic cancer treatment: why immunotherapies that work spectacularly in other cancers so often fail here. The researchers found that in some clones, the TIGIT gene was more active, producing proteins that help cancer evade immune detection. In those same clonal cells, activity of the PD1 gene was suppressed. Because several modern immunotherapies are designed to target PD1, its suppression may help explain why such treatments are rarely effective against pancreatic ductal adenocarcinoma. The clones, in effect, have found a molecular back door around the immune system’s most commonly exploited checkpoint.

Dr. Despoina Kalfakakou, a postdoctoral research fellow at NYU Grossman School of Medicine and Perlmutter Cancer Center who led the investigation, said the 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. She noted that the findings suggest targeting the mechanisms underlying tumor evolution, including MYC, may help restrain the cancer’s rapid progression. The implication is profound: rather than attacking a single static target, future therapies may need to anticipate and block the very processes that allow tumors to change shape.

Dr. Aristotelis Tsirigos, the study’s co-senior investigator and a professor in the Departments of Medicine and Pathology at NYU Grossman School of Medicine, said the research suggests that single-cell clonal analysis offers a better approach to understanding complex cancers as they develop over time, by mapping how tumors evolve and adapt at each stage of disease progression. Tsirigos, who also serves as co-director of the Division of Precision Medicine and director of NYU Langone’s Applied Bioinformatics Laboratories, added that the results highlight the critical role of clonal diversity, genetic plasticity, and interactions with the tumor’s microenvironment in shaping the biology of human pancreatic ductal adenocarcinoma. The tumor’s surroundings, in this view, are not passive scenery but active participants in the cancer’s ability to survive and spread.

The findings arrive at a moment of cautious optimism for a disease that has long defied progress. Dr. Tsirigos noted that clinical trials using MYC inhibitors or TIGIT inhibitors for pancreatic ductal carcinoma and other cancers are already underway, and that the team’s latest findings should encourage larger investigations into different cancer cell states and how to direct treatment toward them. If those trials succeed, the strategy could mark a turning point: instead of chasing an ever-changing target with blunt instruments, oncologists might one day close off the escape routes that pancreatic cancer cells rely on. Funding for the study was provided by National Institutes of Health grants P30CA016087 and R01CA245005, as well as the Sky Foundation, with collaborating researchers from Oregon Health and Science University and the University of California San Diego contributing to the work.

Subject of Research: Clonal evolution and genetic plasticity in pancreatic ductal adenocarcinoma

Article Title: Continuously evolving cells help pancreatic cancer evade treatment and spread

Article References: Continuously evolving cells help pancreatic cancer evade treatment and spread. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: pancreatic cancer, pancreatic ductal adenocarcinoma, single-cell analysis, clonal evolution, MYC, TIGIT, PD1, immunotherapy resistance, tumor heterogeneity, metastasis, drug resistance, Nature Genetics