Researchers Map Pancreatic Cancer Clones Driving Treatment Resistance

Researchers from NYU Grossman School of Medicine and UC San Diego Health have mapped how pancreatic ductal adenocarcinoma cells evolve within tumors, revealing distinct cancer clones that drive treatment resistance and spread. The Nature Genetics study analyzed 443,451 cells from 62 tumors in 59 people with pancreatic cancer.

According to the researchers, the single-cell analysis showed that tumors contain multiple genetically different clones that develop separate behaviors, including immune evasion and metastatic potential. The study also examined matched samples from six tumors before and after chemotherapy to track evolutionary changes.

Diane Simeone, director of Moores Cancer Center and co-senior author of the study, said the findings explain why pancreatic cancer remains difficult to treat.

"Pancreatic cancer is one of the most aggressive human malignancies, with a dismal survival rate and very few resources and tools to combat it. Our work shows that within a single tumor, different clones are evolving in parallel, taking on different identities and interacting with the immune and stromal landscape in distinct ways. That heterogeneity is why the disease is so hard to treat, because every tumor is unique," said Diane Simeone, director of Moores Cancer Center.

The research identified genetic shifts linked to changes between classical and basal tumor states. According to the study, increased MYC activity helped aggressive basal cells maintain their identity, while blocking MYC restored classical features and immune-response pathways.

The authors described the single-cell findings as a detailed view of tumor diversity.

"Revealing a diverse set of clones, or clusters of tumor cells that have a similar genetic makeup," said the study authors.

Experiments in mouse models and human tumor-derived systems showed that reducing MYC activity changed cancer cell behavior. The researchers also found some clones increased TIGIT activity, producing signals associated with immune evasion.

"Clonal heterogeneity is part of why pancreatic cancer is so difficult to treat, but it also presents us with opportunities to discover more precise and effective therapies. When different clones within the same tumor evolve in different directions, they create multiple opportunities for tumors to evade treatment. Understanding this evolution is key to designing treatments that stay ahead of the disease," said Diane Simeone, professor of surgery at UC San Diego School of Medicine.

Aristotelis Tsirigos, professor of medicine and pathology at NYU Grossman School of Medicine and co-director of the Division of Precision Medicine, said the study provides new insight into cancer evolution.

"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 Aristotelis Tsirigos, professor of medicine and pathology at NYU Grossman School of Medicine.

The researchers reported that MYC disruption changed aggressive cancer cells toward a less aggressive state and increased exposure to immune cells.

"Reverted the cells to the less aggressive classical form and exposed them to more immune cells, potentially making them more vulnerable to immune attack," said the researchers.

Simeone also leads the Pancreatic Cancer Early Detection Consortium, which includes more than 60 partner centers sharing data, biospecimens, and imaging for pancreatic cancer research.

"Moores Cancer Center is redefining what's possible in pancreatic cancer. By combining fundamental research in the lab with large-scale clinical trials and global collaboration, we're building a research ecosystem that will help us find pancreatic cancer faster, treat it more effectively, and transform outcomes for patients," said Diane Simeone, director of Moores Cancer Center.