Pancreatic Cancer Keeps Rewriting Its DNA to Resist Treatment
Pancreatic cancer constantly reshuffles its genetic makeup, and that helps it spread and resist treatment, a single-cell study of nearly half a million tumour cells has found. The work by researchers at NYU Langone Health and its Perlmutter Cancer Center appeared on October 13 in Nature Genetics.
The team studied pancreatic ductal adenocarcinoma, the most common form of the disease and a particularly hard one to treat: nearly 85 percent of patients die within five years of diagnosis. Researchers have already linked more than half a dozen genes to it, but how the cancer develops and adapts has remained largely unclear.
Looking at cells one by one
Instead of studying tumour cells in large batches, the researchers examined them individually. That let them see how different populations of cancer cells change their DNA as the disease progresses.
Tumours turned out to contain many distinct clones, each a group of cancer cells with similar genetic features. Their behaviour can differ sharply. Some clones acquire changes that let them withstand treatment, while others become better at invading surrounding tissue and spreading through the body. The authors conclude that the cancer's ability to keep reorganising its genetic material plays a central role in both treatment resistance and metastasis, the spread of tumours.
The finding also fills a gap in the standard picture. Earlier studies sorted pancreatic cancer cells into two types, classical (less aggressive) and basal (more aggressive), but because they looked at large collections of cells together, they could not fully explain how cells move from one type to the other. The new data show that genetic changes inside individual tumours allow cells to shift between the two states, which may make the disease more dangerous as it advances.
MYC: a gene that can be switched off
One of the key findings concerns MYC, a gene that was unusually active in some of the most aggressive cell populations. In additional laboratory experiments, the researchers blocked MYC activity in aggressive basal pancreatic cancer cells. The cells moved back toward the less aggressive classical state. They also became more exposed to immune cells, which suggests the immune system could find and attack them more easily. Further research is needed, but the results point to MYC as a promising target for future treatments.
"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 lead investigator Despoina Kalfakakou, a postdoctoral research fellow at NYU Grossman School of Medicine and Perlmutter Cancer Center.
Why immunotherapy often fails
The study also offered clues to how the cancer hides from the immune system, which may explain why it often responds poorly to immunotherapy. Certain clones showed increased activity of the TIGIT gene, which is associated with proteins that help tumours escape immune detection. At the same time, these clones had reduced activity of the PD1 gene. That combination may help explain why immunotherapies aimed at PD1 have shown limited effectiveness against pancreatic cancer.
Co-senior investigator Aristotelis Tsirigos, a professor in the Departments of Medicine and Pathology at NYU Grossman School of Medicine, said clinical trials of drugs that inhibit MYC or TIGIT are already under way for pancreatic ductal carcinoma and other cancers. He said the results underscore the need for larger studies of the different states cancer cells can adopt, and of how treatments might be tailored to each. Single-cell clonal analysis, he added, offers a better way to understand complex cancers as they develop over time.
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