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Troy+ stomach stem cells in homeostasis, repair and pathogenesis

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Hunting for the genes that can switch off cancer

When the body repairs damage to tissue in the stomach lining, the process can backfire, leading to tumours. Understanding what switches that process on could pave the way to therapies to treat gastric cancer.

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Stomach cancer has a significant impact on public health: it is the seventh most commonly diagnosed cancer and the fifth most frequent cause of cancer death in Europe. Three in four of those diagnosed with stomach cancer do not survive past 5 years. The EU supported Troy Stem Cells project sought a better understanding of an unusual cell type found in the stomach, which can switch from a quiescent state to an actively proliferating one in order to repair tissue damage. “We were trying to shed light on the understanding of how stomach stem cells maintain a balance between tissue injury repair and homeostasis,” says project coordinator Bon-Kyoung Koo. “And also, how aberrant stem cell proliferation leads to tumorigenesis.”

Genetic switch

Because Troy+ stem cells are able to alternate between quiescent and actively dividing states, they offer a model for understanding how cancer cells escape biological control to divide continuously. Troy+ stem cells have also been identified as playing a role in the development of spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor of stomach cancer. Prior to this study, it wasn’t clear how Troy+ stem cells switched between their two modes. However, Koo and his team at the Austrian Academy of Sciences were able to identify a molecular switch as the one responsible. “We have found that a well-known cell cycle regulator is highly expressed in resting stem cells, but is rapidly lost upon tissue injury, leading to active proliferation,” he adds. To study the progression and treatment of different types of stomach cancer, the team and their collaborator, Daniel Stange at the University Hospital Carl Gustav Carus in Dresden, Germany, engineered mice that developed similar gastric cancers. This allowed them to study the tumours both in vivo and in vitro, using organoids derived from the animals’ stem cells. “Using this model, we could learn requirements for stomach cancer progression, and potential therapeutic approaches to cure gastric cancer,” explains Koo.

EU funding

The project was supported by the European Research Council. Koo says this grant was particularly useful in setting up strong collaborations with researchers in Dresden and Cambridge. “The ERC funds have also been used in recruiting brilliant young scientists as postdoctoral researchers and research assistants,” he notes. “And we have published a number of papers ranging from pure basic science to more translational research.” Through the research, the team were able to develop more than 20 human and mouse cancer organoids to model the disease and test out potential treatments. Next, the team plans to use these to further investigate the genes and molecular mechanisms identified through the Troy Stem Cells project. It’s hoped that a better understanding of these processes will lead to new therapeutic avenues in the battle against gastric cancers.

Keywords

Troy Stem Cells, cancer, stomach, gastric, organoids, proliferation, tissue, injury, switch, Troy+ stem cells

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