Researchers map how pancreatic tumors rewire DNA to dodge therapy
A team at NYU Langone uncovered how pancreatic ductal adenocarcinoma cells constantly remodel their genome, creating aggressive clones that resist treatment, and showed that blocking the MYC gene can reverse this process.
Investigators examined 443,451 individual cells from 62 pancreatic ductal adenocarcinoma samples, uncovering two to eleven distinct clones per tumor that shift between classical and basal phenotypes as the disease progresses. Genetic profiling highlighted MYC as a driver of the basal, highly aggressive clone, and laboratory experiments showed that MYC inhibition reprogrammed these cells toward a classical, less invasive profile that is more visible to immune cells.
The research also found that certain clones up-regulate TIGIT while down-regulating PD1, offering a possible explanation for the limited success of PD1-targeted immunotherapies in this cancer. The work underscores the importance of single-cell clonal analysis for understanding tumor evolution and points to MYC and TIGIT as promising targets in upcoming clinical trials. Funding came from the Sky Foundation and NIH grants, and collaborators included researchers from Oregon Health and Science University and the University of California San Diego.
Why it matters
Understanding the genetic plasticity of pancreatic cancer could lead to therapies that stop its spread and improve survival rates.
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