Pancreatic Cancer Can Change Its “Genetic Strategy”: Study Identifies Key Mechanisms

Researchers at NYU Langone Health and the Perlmutter Cancer Center in the United States studied pancreatic ductal adenocarcinoma, one of the most difficult forms of cancer to treat. According to the authors, nearly 85% of patients with this disease die within five years of diagnosis. The findings were published in the journal Nature Genetics.

The scientists examined gene activity in 443,451 individual cells collected from 62 tumors in 56 patients. For six patients, samples were taken both before and after chemotherapy, allowing the researchers to compare the characteristics of tumor cells at different stages of treatment.

Previously, researchers generally divided the cells of this tumor type into two main subtypes: classical, which is typically less aggressive, and basal, which is associated with a poorer disease course. However, it remained unclear how cells transition from one state to the other.

The new analysis showed that a single tumor can contain several genetically distinct groups of cells, known as clones. On average, the tumors examined contained between two and 11 combinations of classical and basal cell clones. These groups behaved differently: some acquired characteristics associated with treatment resistance, while others developed traits linked to faster spread.

One of the key factors identified was the MYC gene, whose activity increased in more aggressive groups of tumor cells. In additional experiments, blocking MYC in basal cells caused them to shift toward the less aggressive classical state. At the same time, these cells became more accessible to immune cells that could potentially attack the tumor.

The researchers also detected increased activity of the TIGIT gene in some clones. This gene is associated with mechanisms that help tumor cells evade detection by the immune system. At the same time, PD1 gene activity was reduced in the same cell groups. This may partly explain why certain types of immunotherapy targeting the PD-1 pathway are often ineffective against pancreatic cancer.

According to the authors, the findings indicate that a tumor should not be viewed as a uniform mass of cells: different cell populations may use distinct mechanisms to survive and resist treatment.