Half-million-cell study maps pancreatic cancer’s genetic shifts

Nearly half a million individual tumor cells have been analyzed to uncover the mechanisms allowing pancreatic cancer to continuously reshape its genetic makeup, thereby evading therapeutic intervention. This extensive study, conducted by researchers at NYU Langone Health and its Perlmutter Cancer Center, focuses on pancreatic ductal adenocarcinoma, a disease notorious for its lethality, claiming nearly 85 percent of patients within five years of diagnosis.

Clonal diversity drives resistance

The investigation provides granular insights into how subpopulations of cancer cells reconfigure their DNA over time. By analyzing single tumor cells rather than bulk groups, the team identified diverse clones—clusters with similar genetic profiles—that exhibit striking behavioral differences. Some clones evolve to resist therapy, while others acquire the capacity for rapid spread. These findings indicate that ongoing genetic reshaping fuels both treatment resistance and metastasis.

Prior research had categorized pancreatic cancer cells into two subtypes: classical (less aggressive) and basal (more aggressive). However, those studies failed to explain how cells shift between these categories. The new data demonstrates that genetic reconfiguration within the tumor enables this transition. Published online in Nature Genetics on Oct. 13, the study pinpointed specific genetic changes emerging during tumor evolution, notably increased activity of the MYC gene in aggressive cell populations.

MYC inhibition alters cell behavior

Experiments involving pancreatic basal tumor cells revealed that blocking MYC activity reverted the cells to the less aggressive classical form. This change also exposed the cells to more immune cells, potentially increasing their vulnerability to immune attack. Despoina Kalfakakou, PhD, the study’s lead investigator and postdoctoral fellow at NYU Grossman School of Medicine and Perlmutter Cancer Center, stated that the work offers the most detailed view to date of pancreatic ductal adenocarcinoma, showing how continuous genetic reshaping drives tumor evolution throughout the disease course.

Kalfakakou noted that targeting mechanisms underlying tumor evolution, including MYC, may help restrain the cancer’s rapid progression. Aristotelis Tsirigos, PhD, co-senior investigator and professor in the Departments of Medicine and Pathology at NYU Grossman School of Medicine, emphasized that single-cell clonal analysis provides a superior approach to understanding complex cancers as they develop. He explained that mapping how tumors evolve and adapt at each stage of disease progression is critical.

Immune evasion mechanisms identified

Tsirigos, who also serves as co-director of the Division of Precision Medicine and director of NYU Langone's Applied Bioinformatics Laboratories, highlighted the essential role of clonal diversity, genetic plasticity, and interactions with the tumor microenvironment in shaping human pancreatic ductal adenocarcinoma biology. Among other key findings, the study showed how cell clones influence the tumor’s ability to evade immune detection, possibly explaining why this carcinoma resists immune therapy.

In some clones, the TIGIT gene was found to be more active, producing proteins that assist cancer in avoiding immune detection. Concurrently, activity of the PD1 gene was suppressed in these same clonal cells. This suppression may account for the limited effectiveness of certain immunotherapies targeting PD1. Clinical trials using MYC inhibitors or TIGIT inhibitors for pancreatic ductal carcinoma and other cancers are currently underway, according to Dr. Tsirigos. He suggested that these latest findings should encourage larger investigations into different cancer cell states and targeted treatments.

Study methodology and scope

Researchers analyzed genetic activity via transcriptomics in clones comprising 443,451 single cells taken from 62 tumors in 56 men and women diagnosed with pancreatic ductal adenocarcinoma. Six patients provided tumor samples both before and after chemotherapy. Traditionally, cells have been analyzed in bulk to detect upticks and decreases in gene activity, rather than individually as done in this latest analysis.

Single-cell analysis indicated that individual tumors contained an average of between two and 11 mixes, or clones, of basal and classical tumor cells. By tracing the clones' genetic origins based on gene activity, researchers linked cell copy variations to tumor composition. This method allowed them to identify which genes, such as MYC and TIGIT, were most active at different stages of disease progression.