Scientists have explained the resistance of pancreatic cancer to treatment

Pancreatic ductal adenocarcinoma cells can change as the disease develops, forming groups with different properties within the same tumor. This heterogeneity helps explain the resistance to therapy and the ability of cancer to spread. These conclusions were reached by researchers from the University of California at San Diego and New York University, who studied the activity of genes in almost half a million individual cells. Why cells of the same tumor react differently to treatment, what role the MYC gene plays and how new data can help in the search for therapy - in the Izvestia material.

One tumor — different groups of cells

Ductal adenocarcinoma of the pancreas, or PDAC, is one of the most aggressive cancers. According to the university's report, more than 85% of patients with this form of cancer die within five years of diagnosis.

One of the difficulties of treatment is related to the fact that the tumor is heterogeneous. It contains clones, groups of cancer cells with similar genetic characteristics. At the same time, the properties of different clones may differ significantly: some acquire resistance to therapy, while others acquire the ability to spread faster.

The stromal environment refers to the supporting tissues and cells around the tumor. Together with immune cells, they form its microenvironment. The researchers were interested in how the differences between the clones are related not only to the behavior of the cancer itself, but also to its interaction with this environment.

According to Simeone, this heterogeneity is one of the reasons why the disease is difficult to treat. Even within a single tumor, several groups of cells can simultaneously develop, with different possibilities for preservation and further growth.

What did the analysis of almost half a million cells show?

The scientists studied the activity of genes in 443,451 individual cells from 62 tumor samples obtained from several dozen patients. This approach allowed us to consider differences that are more difficult to detect when analyzing a large number of cells together.

When examining the entire sample, researchers get a generalized picture of the activity of the genes. However, it may conceal individual cell groups with significantly different characteristics. The analysis of single cells helps to separate these groups and compare their properties.

The New York University report clarifies that samples were received from six patients before and after chemotherapy. This made it possible to compare the composition of the tumor at different stages of treatment. It also says that from two to 11 clones were detected in individual tumors. As a result, the researchers found marked differences between the cell populations. Their conclusion is that changes in the genetic characteristics of the tumor are associated with its evolution, drug resistance, and metastasis.

At the same time, almost half a million cells studied should not be confused with the number of patients. A large amount of cellular data allows us to describe the tumor heterogeneity in detail, but by itself does not prove the effectiveness of any treatment.

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How cancer becomes more aggressive

In studies of ductal adenocarcinoma, two main molecular subtypes are usually distinguished: classical and basal. Classical is considered less aggressive, basal is considered more aggressive. The new work focuses, among other things, on how cells can transition between these states.

The analysis showed that genetic changes inside the tumor allow its cells to change their properties. Therefore, the division into two subtypes does not always describe the complexity of the disease: different cell groups may be present in the same tumor, which continue to develop.

This is essential for understanding resistance to therapy. If different clones have different properties, the result of exposure to one group of cells does not necessarily characterize the reaction of the entire tumor. That is why the authors consider its evolution as an important part of the search for new treatment approaches.

Why did the MYC gene attract attention?

One of the key results was the detection of increased MYC activity in aggressive basal populations of tumor cells. This gene is already known as one of the factors involved in the development of pancreatic cancer.

In additional experiments, the scientists blocked the activity of MYC. After that, the cells acquired signs of a less aggressive classical state. At the same time, the researchers observed an increase in the presence of immune cells, which could potentially make the tumor more vulnerable to an immune response.

Thus, MYC attracted attention for two reasons at once: its activity is associated with the aggressive properties of cancer cells, and its suppression was accompanied by changes in their condition and immune environment.

How the tumor interacts with the immune system

Another area of work is related to the mechanisms that help tumors avoid an immune response. The university report highlights TIGIT and PD-1, molecules involved in regulating the activity of the immune system.

The authors attribute the differences found in these mechanisms to the characteristics of tumor clones. They suggest that such features may partially explain why PD-1-targeted immunotherapy is rarely effective in ductal adenocarcinoma of the pancreas.

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This conclusion should be considered as a possible explanation that requires further verification. It does not establish the sole reason for the weak response to immunotherapy and does not prove that exposure to TIGIT will be effective for all patients. The more general result of the work is that different clones interact differently with the immune environment. Therefore, to study the disease, it is important to take into account not only the characteristics of cancer cells, but also the processes taking place around them.

What does the discovery change for finding a cure?

The study offers a more detailed look at ductal adenocarcinoma: its development is associated with changes in individual cell groups, transitions between molecular states, and interactions with the microenvironment.

This approach may help to better identify potential therapy targets. At the same time, treatment developers will have to take into account that different groups of cells inside the same tumor are able to develop in different directions.

The new work does not represent a ready-made treatment regimen. Its importance lies in identifying mechanisms that can be verified in further research. In particular, the experimental results provide a basis for a more detailed study of the effects on MYC and TIGIT-related immune processes.

The next stage will be crucial for patients: confirmation that influencing these mechanisms helps control the disease and improves treatment outcomes. So far, scientists have obtained a more detailed picture of how the tumor is changing and why its cellular diversity makes therapy difficult.