2024/09/05
Keio University School of Medicine
A research team led by Professor Toshiro Sato and Associate Professor Masayuki Fujii of the Department of Biochemistry, Keio University School of Medicine, has successfully established pancreatic cancer "organoids," which are miniature versions of organs, from patients with highly malignant pancreatic cancer. They discovered that these organoids can proliferate without the growth signal known as Wnt. The team elucidated that these pancreatic cancers undergo malignant transformation into tissues exhibiting a pathological profile called "adenosquamous carcinoma" due to epigenetic changes caused by the tumor microenvironment, such as hypoxic conditions.
The research team established organoids from pancreatic cancer patient tissues at various stages, creating a library totaling 65 cases. Analysis of this library revealed that while most pancreatic cancers require activation of signals by the growth factors Wnt/R-spondin, a small number of pancreatic cancer organoids can proliferate without them. Pancreatic cancer organoids dependent on Wnt/R-spondin exhibit the histopathological structure of adenocarcinoma, a common histological type of pancreatic cancer. In contrast, Wnt/R-spondin-independent pancreatic cancers showed a solid, multilayered morphology and expressed squamous cell markers not typically present. The team also determined that genetic mutations in the histone demethylase KDM6A or its reduced activity due to hypoxic conditions promote these changes in tissue structure and growth factor-independent proliferation, causing malignant transformation. Furthermore, the research team demonstrated that EZH2 inhibitors, which suppress histone methylation, are promising as a therapeutic agent for highly malignant pancreatic cancer. This raises expectations for establishing new treatment methods for pancreatic cancer, which has a high mortality rate that continues to rise.
The details of this research were published in the online edition of the British scientific journal Nature Cell Biology on September 4, 2024 (UK time).
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