Scientists discover how pancreatic cancer rewrites its DNA to escape treatment
Scientists have discovered how pancreatic cancer cells continually reshape their genetic makeup to become more aggressive, spread, and evade treatment. In laboratory experiments, blocking a key gene reversed some of these dangerous changes, revealing a potential new way to fight the deadly disease.
Key points
- NYU Langone researchers examined 443,451 individual cells from 62 pancreatic tumors to map genetic changes.
- Pancreatic tumors contain 2 to 11 distinct clones that shift between classical and basal states.
- Blocking MYC in aggressive cells pushed them toward a less aggressive state more visible to the immune system.
Scientists at NYU Langone Health and its Perlmutter Cancer Center have uncovered new details about how pancreatic cancer changes its genetic makeup to become more aggressive, spread and resist treatment. The study, published October 13 in Nature Genetics, examined nearly half a million individual cancer cells and focused on pancreatic ductal adenocarcinoma, which kills nearly 85 percent of patients within five years of diagnosis.
By studying tumor cells individually rather than in large groups, the team found that pancreatic tumors contain distinct cell populations called clones. Some clones develop changes that help them withstand treatment, while others become better equipped to invade tissues and spread.
Gene activity and cell states
The researchers examined gene activity in 443,451 individual cells from 62 tumors belonging to 56 patients. Six patients also provided tumor samples before and after chemotherapy. Each tumor contained approximately two to 11 distinct clones made up of varying combinations of classical and basal cancer cells.
The study identified MYC as a gene with heightened activity in some of the most aggressive cell populations. When researchers blocked MYC in aggressive basal cells, the cells shifted back toward the less aggressive classical state and became more exposed to immune cells. Certain clones also showed increased TIGIT activity and reduced PD1 activity, which may help explain why PD1-targeting immunotherapies have shown limited effectiveness.
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
— Despoina Kalfakakou
What researchers said
Study lead investigator Despoina Kalfakakou said the work provides the most detailed view to date of how genetic reshaping drives tumor evolution. She said targeting mechanisms behind tumor evolution, including MYC, may help restrain the cancer's rapid progression.
Co-senior investigator Aristotelis Tsirigos said clinical trials of drugs that inhibit MYC or TIGIT are already underway for pancreatic ductal carcinoma and other cancers. He said the findings underscore the need for larger studies examining the different states cancer cells can adopt and how treatments might be tailored to target them.
