Scientists at NYU Langone Health have identified the specific genetic mechanisms that allow pancreatic cancer to rewrite its DNA, enabling the disease to resist treatment and spread throughout the body. The study, published in Nature Genetics, provides the most detailed look yet at how individual tumor cells evolve over time.
Pancreatic ductal adenocarcinoma is one of the deadliest forms of cancer, with nearly 85 percent of patients dying within five years of diagnosis. Previous research struggled to explain how the disease adapts because it typically analyzed large groups of cells together. This approach masked the subtle differences between individual cancer populations.
The new research examined 443,451 individual cells collected from 62 tumors belonging to 56 patients. By analyzing each cell separately, the team discovered that tumors contain distinct populations of cancer cells known as clones. These clones behave differently, with some developing resistance to chemotherapy while others become better equipped to invade surrounding tissues.
Genetic Shifts Drive Aggression
Researchers previously categorized pancreatic cancer cells into two main groups: classical and basal. Classical cells are generally less aggressive, while basal cells are more dangerous and prone to spreading. The new findings explain how cancer cells move between these states.
The study identified that genetic changes within individual tumors allow cells to shift from the classical state to the more aggressive basal state. This transition is driven by the MYC gene, which showed heightened activity in the most dangerous cell populations.
In laboratory experiments, the researchers blocked MYC activity in aggressive basal cells. The cells shifted back toward the less aggressive classical state. This change also made the cancer cells more visible to the immune system, suggesting they could become easier targets for immune-based therapies.
“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 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.”
Immune System Evasion Mechanisms
The investigation also uncovered how pancreatic cancer hides from the immune system. Researchers found that certain cancer cell clones showed increased activity of the TIGIT gene. This gene 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 helps explain why immunotherapies designed to target PD1 have shown limited effectiveness against pancreatic cancer. The disease often responds poorly to these treatments because the cancer cells use different mechanisms to avoid immune attack.
Aristotelis Tsirigos, PhD, a professor in the Departments of Medicine and Pathology at NYU Grossman School of Medicine, emphasized the importance of understanding these complex interactions. “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,” Tsirigos said. “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.”
Clinical trials investigating drugs that inhibit MYC or TIGIT are already underway for pancreatic ductal carcinoma and other cancers. The findings underscore the need for larger studies to examine how different cancer cell states respond to treatment and how therapies can be tailored to target specific genetic changes.
Source: ScienceDaily
