title: Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior.
abstract: 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 ApcMin/+(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.
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.|Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.|Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto 606-8507, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.|Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Semi
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yagi
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Itakura
authors.affiliation: Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kunisada
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.|Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Knut
authors.initials: K
authors.lastname: Woltjen
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto 606-8507, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Haga
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.|Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.|Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo 100-0004, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; y-yamada@cira.kyoto-u.ac.jp.|Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000483:Alleles; D000818:Animals; D019070:Cell Lineage / Q000235:genetics; D000066670:Cell Plasticity / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D017491:Genes, APC / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D039904:Pluripotent Stem Cells / Q000378:metabolism
keywords: cancer epigenetics; colon cancer; iPS cell; mouse model; plasticity