研究セミナー Brain tumor modeling using in vivo somatic gene transfer approaches

Rigid animal models of cancer are one of powerful tools for understanding of molecular mechanisms underlying how normal cells transform into malignant cells. Those models further offer us the opportunity to examine how we could prevent tumor progression with drug treatment. Despite these advantages, we often face the difficulty in generation of animal models that molecularly recapitulate human counterparts, since causal mutation(s) in cancer are usually hidden in a large number of passive mutations. While genetically engineered mouse models have utilized to identify real oncogenes and tumor suppressor genes, germline models are costly and time-consuming. To bypass these problems, I would here introduce in vivo electroporation-based somatic gene transfer methods for brain tumor modeling. In the first part, I will show the first ependymoma animal model that was caused by dysregulation of the Hippo pathway. Using transposon-based non-germline gene transduction, we developed tumors in situ under the physiologically relevant condition. The model would be a good example for preclinical studies, in which tumor growth is monitored by in vivo bioluminescence. In the second part, I will show the example of CRISPR/Cas9-engineered in vivo somatic mutations to model SHH-subgroup medulloblastoma. Using this model, I will further discuss how chromatin modifiers are involved in medulloblastoma formation. Collectively, these approaches provide a convenient platform for not only in vivo functional analysis but also effective preclinical studies, which would accelerate establishment of new therapeutic methods.