Pancreatic cancers- one of the most lethal cancers, has an exceptionally high mortality rate. One reason is that effective treatments are hard to find because different cancer cells in the same tumor can respond very differently to the same treatment. Pancreatic cancer cells are very varied, not just in their shape but also in how dangerous they are, such as how aggressive they grow.
Pancreatic cancer cells can be divided into epithelial and mesenchymal types based on appearance and genetic characteristics.
Maximilian Reichert, Professor of Translational Pancreatic Cancer Research at the TUM University Hospital Klinikum rechts der Isar, said, “However, the tumor cells can change their structure and function during the illness. It has been shown that these two main categories have a wide range of manifestations. These can vary greatly in their biological characteristics.”
A team led by Reichert has, for the first time, recreated the complex shape of pancreatic cancer cell clusters in the lab. In the body, tumor cell clusters are shaped like glands, with many branches resembling ducts. However, when individual tumor cells are taken and used to grow artificial 3D cell clusters in the lab, called organoids, the traditional method only produces round structures. These don’t have the same shape or properties as the actual tumor clusters in the body.
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Aristeidis Papargyriou, the study’s lead author, said, “Now we can generate organoids that greatly resemble the real, branched cell clusters found in the body. This lets us reproduce the complexity of pancreatic cancer in the laboratory for the first time.”
The team used machine learning to group the newly grown organoids based on their shapes. They found different types within the two main subtypes, epithelial and mesenchymal. In simple terms, these groups within the same tumor type look different and behave differently in terms of how aggressive they are.
At first, they worked with organoids made from mouse tumor cells. “For example, ‘star-like organoids’ are round in the center but have many branches at the edges, while ‘TEBBO organoids’ have thick branches with hollow centers and small buds at the ends.”
These different types don’t just look different—they also behave differently. They grow differently, have unique metabolic activities, and respond in distinct ways when oxygen-deprived. Most importantly, they react differently to treatments: for instance, the star-like organoids were resistant to the chemotherapy used in the study but were highly affected by radiation.
The team then applied this technology to tumor cells from pancreatic cancer patients. In the lab, they grew several different types of organoids from these cells and tested them with various treatments to find weaknesses in the cancer cells.
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The new organoids could help create more personalized treatments. Doctors could tailor therapies more effectively by understanding the specific phenotypes in a patient’s tumor and how they respond to different treatments.
The researchers are also exploring a second strategy to improve treatments. “Treating multiple tumor phenotypes at once is challenging. If we use the same medication for all, they might react differently or change into other phenotypes, making them resistant to the treatment,” says Reichert.
“That’s why we thought of reducing the number of phenotypes in a tumor. Ideally, we’d be left with just a few stable ones, and then we could develop treatments specifically targeting those remaining phenotypes.”
The researchers tested this strategy on the new organoids by adding different drugs. Some phenotypes were suppressed, while others changed into related phenotypes or developed new ones. Only two main phenotypes remained as planned, and they no longer changed. In the future, the researchers aim to identify substances that can specifically target and treat these remaining phenotypes and continue to refine this approach.
Journal Reference:
- A. Papargyriou, M. Najajreh, et al. Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma”; Nature Biomedical Engineering (2024); DOI: 10.1038/s41551-024-01273-9