A new analysis of nearly half a million cells from dozens of pancreatic tumors, led by researchers at UC San Diego Moores Cancer Center and New York University (NYU), reveals how pancreatic cancer cells continuously reshape their genetic makeup over time, enabling them to evade treatment. The study, published in the journal Nature Genetics, focused on pancreatic ductal adenocarcinoma (PDAC), a difficult-to-treat pancreatic cancer known to kill more than 85 percent 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 Diane Simeone, MD, 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."
While more than half a dozen genes to date have been implicated in PDAC, this new analysis of single tumor cells provides new insights into how subpopulations of pancreatic cancer cells reconfigure their DNA within tumors over time. Traditionally, cells have been analyzed in bulk for increases and decreases in gene activity, not individually.
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. These clones showed striking differences in behavior, with some evolving to resist therapy and others acquiring the ability to spread rapidly. The findings suggest that ongoing reshaping of the cancer cells' DNA fuels both treatment resistance and metastasis.
"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 study co-senior author Aristotelis Tsirigos, PhD, professor of medicine and pathology at NYU Grossman School of Medicine and co-director of the Division of Precision Medicine.
Past research analyzing bulk groups of pancreatic cancer cells has focused on separating them into two subtypes — the less aggressive classical type, and the more aggressive basal type. However, prior research has not explained how cancer cells shift between these subtypes. The new findings show that genetic reconfiguration within a tumor enables cancer cells to transition between subtypes.
The study identified specific genetic changes that emerge during tumor evolution, including increased activity of the MYC gene — a well-established driver of pancreatic cancer — in aggressive basal tumor cell populations. Further experiments showed 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.
The researchers also found that in some clones, the TIGIT gene was more active, producing proteins that help cancer evade immune detection. In the same clonal cells, activity of the PD-1 gene was found to be suppressed, which may help explain why immunotherapies that target PD-1 are rarely effective against PDAC.
"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 UC San Diego 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."
In addition to offering new insights into PDAC and suggesting possibilities for treatment, the research also builds on UC San Diego's established leadership in pancreatic cancer research and care. For example, Simeone is also director of the Pancreatic Cancer Early Detection (PRECEDE) Consortium, the largest initiative of its kind worldwide, 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," said Simeone. "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."
Read the full study: "Clonal heterogeneity in human pancreatic ductal adenocarcinoma and itsimpact on tumor progression"
Additional co-authors on the study include: Lidong Wang, Qi Su, Sungsik Kim, Hannah Carter and Theodore H. Welling at UC San Diego Moores Cancer Center; Despoina Kalfakakou, Daniel C. Cameron, Emily A. Kawaler, Elektra Manolakos, Xiaohong Jing, Cristina Hajdu, Dylan L. Tamayo, Yoona Shim, Amanda Ackermann, Daniel Weissinger, Rosmel Hernandez, Matthew Beier, Dacia Dimartino, Peter Meyn, Kalina Rice, Shanmugapriya Selvaraj, Cynthia Loomis, Adriana Heguy, Amanda W. Lund and Igor Dolgalev at New York University and Motoyuki Tsuda, Hayley Zimny and Rosalie C. Sears at Oregon Health and Science University.
The study was funded, in part, by the National Institutes of Health (grants [R01CA245005]. [P30CA016087] and a Sky Foundation Seed Award.
