Program

OR7-2

Development of new therapeutic strategy for sporadic or hereditary form of cancer by using patient-derived iPS cells

[Speaker] Eijiro Nakamura:1
1:Medical Innovation Center, Kyoto University Graduate School of Medicine, Japan

Background) It is well known that von-Hippel-Lindau (VHL) gene harbored the E3 ligase activity as a major part of the tumor suppressor function. In fact, polyubiqutinated hypoxia-inducible factor (HIF) by the E3 machinery of VHL is degraded by proteasome under normoxic conditions. Importantly, HIF regulates most of genes mandatory for cell adaption and survival to hypoxia, therefore, VHL plays a major roles in the physiological oxygen-sensing pathway in cells. Since some of HIF target genes such as VEGF or EGFR posse oncogenic activities, dysregulation of HIF through the inactivation of VHL resulted in the development of sporadic or hereditary form of renal cell carcinomas. However, knocking out of vhl alone in mice failed to recapitulate the phenotype of human disease and thus novel experimental model is required for the development of new therapeutic strategy to conquer tumors caused by the mutation of VHL.
Methods) For this purpose, we generated human induced pluripotent stem (iPS) cells from skin fibroblasts or blood cells from patient with VHL disease harboring germline mutation of the gene.
Results and conclusions) As for in vivo experiments, we injected those cells into testes of NOD-SCID mice and found that VHL+/- iPS cells have the ability to differentiate three germ layers, ectoderm, mesoderm, and endoderm. Since all VHL-related tumor cells exhibit VHL-/- genotype, we have disrupted the wild type allele by using CRISPR/Cas9 system. Importantly, established VHL-/- iPS cells highly expressed HIF target proteins and still retained the pluripotency. Collectively, VHL patient derived iPS cells might be useful tools for the recapitulation and the development of new therapeutic approach for VHL-related tumors.

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