Pancreatic cancer cells can reshape their makeup over time, making them one of the most difficult cancers to treat, according to a study published on Tuesday by UC San Diego Moores Cancer Center and New York University.
The study, published Tuesday in the journal Nature Genetics, focused on pancreatic ductal adenocarcinoma (known as PDAC), a difficult-to-treat pancreatic cancer known to kill more than 85% of people within five years of diagnosis.
"Pancreatic cancer is one of the most aggressive human malignancies, with a dismal survival rate and very few resources and tools to combat it," said Dr. Diane Simeone, director of Moores Cancer Center and co-senior author of the study. "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."
By analyzing single tumor cells, the study looks into how they reconfigure their DNA within tumors over time. In the past, most cellular study focus on cells in bulk, rather than individuals.
The new study analyzed genetic activity in 443,451 single cells taken from 62 tumors in 59 people with PDAC, "revealing a diverse set of clones, or clusters of tumor cells that have a similar genetic makeup," the authors write. These clones had striking differences, with some evolving to resist therapy and others acquiring the ability to spread rapidly.
According to the authors, past research analyzing bulk groups of pancreatic cancer cells focused on separating them into two types — the less aggressive classical type, and the more aggressive basal type. However, this earlier research has not explained how cancer cells shift between these types.
One element found is increased activity of the MYC gene — a driver of pancreatic cancer — in aggressive basal tumor cell populations. Experiments found that blocking MYC activity "reverted the cells to the less aggressive classical form and exposed them to more immune cells, potentially making them more vulnerable to immune attack," a statement from UCSD said.
Another gene — the TIGIT gene — could be more active in some cells, producing proteins which make the cancer cells evade detection.
"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," said Simeone, who is also a professor of surgery at UCSD School of Medicine. "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."
Simeone is also director of the Pancreatic Cancer Early Detection Consortium, which brings together more than 60 partner centers collaborating to share data, biospecimens and imaging to detect pancreatic cancer at its earliest stage.
"Moores Cancer Center is redefining what's possible in pancreatic cancer," Simeone said. "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."
