A research group consisting of Yukinori Terada and Norihide Shiro, graduate students of Kyoto University, and Professor Yasuhiro Yamada of the University of Tokyo has succeeded in creating a new brain tumor model using human induced pluripotent stem cells (iPS cells).By analyzing this model, we clarified the pathophysiology of malignant brain tumors in children and developed a new therapeutic strategy aimed at the cause.
Childhood brain tumors are the second most common cancer in children after leukemia.In particular, AT / RT (atypical teratoidoma-like / labdoid tumor) is the most malignant brain tumor found in infancy, with more than half of children dying within a year.Patients have a SMARC B1 gene abnormality.The reason for the characteristic pathophysiology of this tumor and the cause of its increased malignancy are unknown, and there is no effective treatment method that has been established worldwide.
In the study, human iPS cells were mutated with the SMARCB1 gene and transplanted into the brains of immunodeficient mice.When observing the tumor formed in the brain of the mouse when transplanted in the state of undifferentiated iPS cells, it was found that it has AT / RT characteristics such as characteristic rabidoid cells, which is the first human in the world. We succeeded in creating an AT / RT model using cells.
In addition, when examining the characteristics of the AT / RT model, we confirmed "pluripotent stem cell-like gene expression," which is a gene expression pattern similar to iPS cells and embryonic stem cells (ES cells).Experiments with patient specimens have revealed that this is the cause of poor prognosis.
Furthermore, by disrupting and suppressing the function of specific genes (RAD21 gene or EZH2 gene) by drugs, pluripotent stem cell-like gene expression and AT / RT cell proliferation could be suppressed.This treatment strategy has also been shown to be effective against other pediatric malignancies (neuroblastoma, nephroblastoma, hepatoblastoma) with the same characteristics as AT / RT.
This study is expected to lead to the development of new treatments for pediatric brain tumors with poor prognosis for which there is no effective treatment.
Paper information:[Cell Reports] Human pluripotent stem cell-derived tumor model uncovers the embryonic stem cell signature as a key driver in atypical teratoid / rhabdoid tumor
