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Proceedings of the National Academy of Sciences of the United States of America v.114 no.4, 2017년, pp.758 - 763   SCI SCIE
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Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior

Hashimoto, Kyoichi (Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan ); Yamada, Yosuke ( ); Semi, Katsunori ( Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan ); Yagi, Masaki ( ); Tanaka, Akito ( Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan ); Itakura, Fumiaki ( ); Aoki, Hitomi ( Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan ); Kunisada, Takahiro ( ); Woltjen, Knut ( Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan ); Haga, Hironori ( ); Sakai, Yoshiharu ( Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan ); Yamamoto, Takuya ( ); Yamada, Yasuhiro ( Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan );
  • 초록  

    Significance Genotype-linked disease phenotypes are often observed in a cell type-specific manner, implying a cellular context-dependent effect of the genetic aberrations. However, the extent to which cellular context affects the biological consequences of oncogenic mutations is unclear. Here, we reprogrammed colon tumor cells in an Apc Min/+ (adenomatous polyposis coli) mouse model and showed the divergent in vivo consequences of Apc mutation that arise in different cellular contexts. We also showed that the reprogrammed tumor cells remain in a pretumoral microadenoma stage after differentiation into colonic epithelium, suggesting that macroscopic colon tumor cells are reprogrammable into microadenoma cells. Our results underscore the significance of epigenetic regulation on gene expression, cellular plasticity, and cellular behavior in response to cancer-causing mutations. The spectrum of genetic mutations differs among cancers in different organs, implying a cellular context-dependent effect for genetic aberrations. However, the extent to which the cellular context affects the consequences of oncogenic mutations remains to be fully elucidated. We reprogrammed colon tumor cells in an Apc Min/+ (adenomatous polyposis coli) mouse model, in which the loss of the Apc gene plays a critical role in tumor development and subsequently, established reprogrammed tumor cells (RTCs) that exhibit pluripotent stem cell (PSC)-like signatures of gene expression. We show that the majority of the genes in RTCs that were affected by Apc mutations did not overlap with the genes affected in the intestine. RTCs lacked pluripotency but exhibited an increased expression of Cdx2 and a differentiation propensity that was biased toward the trophectoderm cell lineage. Genetic rescue of the mutated Apc allele conferred pluripotency on RTCs and enabled their differentiation into various cell types in vivo. The redisruption of Apc in RTC-derived differentiated cells resulted in neoplastic growth that was exclusive to the intestine, but the majority of the intestinal lesions remained as pretumoral microadenomas. These results highlight the significant influence of cellular context on gene regulation, cellular plasticity, and cellular behavior in response to the loss of the Apc function. Our results also imply that the transition from microadenomas to macroscopic tumors is reprogrammable, which underscores the importance of epigenetic regulation on tumor promotion.


  • 주제어

    iPS cell .   cancer epigenetics .   plasticity .   colon cancer .   mouse model.  

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