Researchers at NYU Langone Health and its Perlmutter Cancer Center have discovered that pancreatic ductal adenocarcinoma constantly changes its genetic makeup through individual cell evolution, allowing clones within tumors to resist treatment and spread throughout the body. Published October 13 in Nature Genetics, the study analyzed nearly half a million individual cancer cells across 62 tumors, revealing how distinct cell populations shift their DNA as the disease progresses.
Single-Cell Analysis Maps 443,451 Individual Tumor Cells
To map how pancreatic cancer adapts over time, investigators examined gene activity using transcriptomics across 443,451 individual cells. These samples came from 56 patients, with six individuals providing tissue both before and after chemotherapy. Traditional methods measure gene activity across large groups of cells. By contrast, this single-cell approach revealed that individual tumors contain roughly two to 11 distinct clones with varying combinations of classical and basal cancer states. The analysis connected DNA copy number differences with specific cell types to pinpoint active genes during disease progression.
MYC Gene Activity Drives Aggressive Tumor States and Treatment Resistance
The investigation identified heightened activity of the MYC gene in the most aggressive cancer cell populations. When researchers blocked MYC activity in laboratory experiments involving aggressive basal pancreatic cancer cells, the cells reverted toward a less aggressive classical state. This shift also increased their exposure to immune cells, indicating they became easier for the immune system to recognize.
TIGIT and PD1 Gene Activity Explains Immune System Evasion
The research uncovered why pancreatic cancer often evades immunotherapies. Certain cancer cell clones showed increased activity of the TIGIT gene, which associates with proteins that help tumors hide from immune detection, alongside reduced activity of the PD1 gene. This unique expression pattern helps explain why therapies targeting PD1 demonstrate limited effectiveness against the disease.
Trials Test Drugs That Inhibit MYC or TIGIT
Clinical trials investigating drugs that inhibit MYC or TIGIT are currently underway for pancreatic ductal adenocarcinoma and other cancers. The work received support from the Sky Foundation and National Institutes of Health grants P30CA016087 and R01CA245005.
Frequently Asked Questions About Pancreatic Cancer Genetic Evolution
What percentage of pancreatic cancer patients die within five years of diagnosis?
Nearly 85 percent of patients diagnosed with pancreatic ductal adenocarcinoma die within five years. The disease remains exceptionally difficult to treat due to its rapid progression and treatment resistance.
How many distinct clones did researchers find inside individual pancreatic tumors?
Individual tumors contained approximately two to 11 distinct clones. These clones consist of varying combinations of classical and basal cancer cells with different behavioral characteristics.
Which institutions and foundations funded the study?
The research received funding from the Sky Foundation and National Institutes of Health grants P30CA016087 and R01CA245005. Investigators from NYU Langone Health, Oregon Health and Science University, and the University of California San Diego contributed to the findings.
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