{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:37:32Z","timestamp":1787067452941,"version":"build-2736575974"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"4","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2017,1,24]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>Apc<\/jats:italic>\n                    <jats:sup>Min\/+<\/jats:sup>\n                    (adenomatous polyposis coli) mouse model and showed the divergent in vivo consequences of\n                    <jats:italic>Apc<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1614197114","type":"journal-article","created":{"date-parts":[[2017,1,5]],"date-time":"2017-01-05T22:10:45Z","timestamp":1483654245000},"page":"758-763","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":19,"title":["Cellular context-dependent consequences of\n                    <i>Apc<\/i>\n                    mutations on gene regulation and cellular behavior"],"prefix":"10.1073","volume":"114","author":[{"given":"Kyoichi","family":"Hashimoto","sequence":"first","affiliation":[{"name":"Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan;"},{"name":"Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan;"},{"name":"Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto 606-8507, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsunori","family":"Semi","sequence":"additional","affiliation":[{"name":"Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan;"},{"name":"Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Yagi","sequence":"additional","affiliation":[{"name":"Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akito","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiaki","family":"Itakura","sequence":"additional","affiliation":[{"name":"Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitomi","family":"Aoki","sequence":"additional","affiliation":[{"name":"Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Kunisada","sequence":"additional","affiliation":[{"name":"Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Knut","family":"Woltjen","sequence":"additional","affiliation":[{"name":"Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan;"},{"name":"Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Haga","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto 606-8507, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiharu","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan;"},{"name":"Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan;"},{"name":"Japan Agency for Medical Research and Development\u2013Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo 100-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan;"},{"name":"Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2017,1,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1126\/science.1174148","article-title":"Common regulatory variation impacts gene expression in a cell type-dependent manner","volume":"325","author":"Dimas AS","year":"2009","unstructured":"AS Dimas, , Common regulatory variation impacts gene expression in a cell type-dependent manner. 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Cell 126, 663\u2013676 (2006).","journal-title":"Cell"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1038\/328614a0","article-title":"Localization of the gene for familial adenomatous polyposis on chromosome 5","volume":"328","author":"Bodmer WF","year":"1987","unstructured":"WF Bodmer, , Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 328, 614\u2013616 (1987).","journal-title":"Nature"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/328616a0","article-title":"Chromosome 5 allele loss in human colorectal carcinomas","volume":"328","author":"Solomon E","year":"1987","unstructured":"E Solomon, , Chromosome 5 allele loss in human colorectal carcinomas. Nature 328, 616\u2013619 (1987).","journal-title":"Nature"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1126\/science.275.5307.1784","article-title":"Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-\/- colon carcinoma","volume":"275","author":"Korinek V","year":"1997","unstructured":"V Korinek, , Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-\/- colon carcinoma. Science 275, 1784\u20131787 (1997).","journal-title":"Science"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1126\/science.275.5307.1787","article-title":"Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC","volume":"275","author":"Morin PJ","year":"1997","unstructured":"PJ Morin, , Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. 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Cell 156, 663\u2013677 (2014).","journal-title":"Cell"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1126\/science.1350108","article-title":"Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene","volume":"256","author":"Su LK","year":"1992","unstructured":"LK Su, , Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668\u2013670 (1992).","journal-title":"Science"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"8927","DOI":"10.1073\/pnas.132275099","article-title":"Intestinal adenomas can develop with a stable karyotype and stable microsatellites","volume":"99","author":"Haigis KM","year":"2002","unstructured":"KM Haigis, JG Caya, M Reichelderfer, WF Dove, Intestinal adenomas can develop with a stable karyotype and stable microsatellites. Proc Natl Acad Sci USA 99, 8927\u20138931 (2002).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.cell.2010.09.010","article-title":"A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs","volume":"143","author":"Kim J","year":"2010","unstructured":"J Kim, , A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143, 313\u2013324 (2010).","journal-title":"Cell"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1101\/gad.287404","article-title":"Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration","volume":"18","author":"Sansom OJ","year":"2004","unstructured":"OJ Sansom, , Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 18, 1385\u20131390 (2004).","journal-title":"Genes Dev"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.cell.2015.05.033","article-title":"Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer","volume":"161","author":"Dow LE","year":"2015","unstructured":"LE Dow, , Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell 161, 1539\u20131552 (2015).","journal-title":"Cell"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/1471-2407-8-162","article-title":"A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine","volume":"8","author":"Reed KR","year":"2008","unstructured":"KR Reed, , A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine. BMC Cancer 8, 162 (2008).","journal-title":"BMC Cancer"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1242\/dev.084103","article-title":"Dose-dependent roles for canonical Wnt signalling in de novo crypt formation and cell cycle properties of the colonic epithelium","volume":"140","author":"Hirata A","year":"2013","unstructured":"A Hirata, , Dose-dependent roles for canonical Wnt signalling in de novo crypt formation and cell cycle properties of the colonic epithelium. Development 140, 66\u201375 (2013).","journal-title":"Development"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/ng1045","article-title":"Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling","volume":"32","author":"Kielman MF","year":"2002","unstructured":"MF Kielman, , Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling. 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Nat Genet 40, 1291\u20131299 (2008).","journal-title":"Nat Genet"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nature11826","article-title":"In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration","volume":"494","author":"Huch M","year":"2013","unstructured":"M Huch, , In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494, 247\u2013250 (2013).","journal-title":"Nature"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nature07935","article-title":"Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche","volume":"459","author":"Sato T","year":"2009","unstructured":"T Sato, , Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262\u2013265 (2009).","journal-title":"Nature"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"13580","DOI":"10.1073\/pnas.0506612102","article-title":"Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis","volume":"102","author":"Yamada Y","year":"2005","unstructured":"Y Yamada, , Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc Natl Acad Sci USA 102, 13580\u201313585 (2005).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1158\/0008-5472.CAN-14-3295","article-title":"Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer","volume":"75","author":"Abu-Remaileh M","year":"2015","unstructured":"M Abu-Remaileh, , Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer. 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Proc Natl Acad Sci USA 101, 13985\u201313990 (2004).","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1614197114","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T12:55:14Z","timestamp":1654606514000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1614197114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,5]]},"references-count":30,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2017,1,24]]}},"alternative-id":["10.1073\/pnas.1614197114"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1614197114","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,5]]},"assertion":[{"value":"2017-01-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}