Premature Termination of Reprogramming In Vivo Leads to Cancer Development through Altered Epigenetic Regulation

• Project/Area Number: 24390096
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kyoto University
• Principal Investigator: YAMADA Yasuhiro 京都大学, iPS細胞研究所, 教授 (70313872)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2012: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: iPS細胞 / エピジェネティクス / リプログラミング / がん / エピゲノム / 脱分化 / 細胞分化 / 分化 / 癌

Outline of Final Research Achievements

Cancer is believed to arise primarily through accumulation of genetic mutations. Although induced pluripotent stem cell (iPSC) generation does not require changes in genomic sequence, iPSCs acquire unlimited growth potential, a characteristic shared with cancer cells. Here, we describe a murine system in which reprogramming factor expression in vivo can be controlled temporally with doxycycline (Dox). Notably, transient expression of reprogramming factors in vivo results in tumor development in various tissues consisting of undifferentiated dysplastic cells exhibiting global changes in DNA methylation patterns. We demonstrate that iPSCs derived from Dox-withdrawn kidney tumor cells give rise to nonneoplastic kidney cells in mice, proving that they have not undergone irreversible genetic transformation. These findings suggest that epigenetic regulation associated with iPSC derivation may drive development of particular types of cancer.

Research Products

• [Journal Article] Dedifferentiation Meets Cancer Development: Proof of Concept for Epigenetic Cancer. (2014)
  • Author(s): Yamada Y, et al
  • Journal Title: Stem Cells Transl Med. Volume: 10 Issue: 10 Pages: 1182-7
  • DOI: 10.5966/sctm.2014-0090
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Application of iPS cell technology to cancer epigenome study: Uncovering the mechanism of cell status conversion for drug resistance in tumor. (2014)
  • Author(s): Matsuda Y, et al
  • Journal Title: Pathol Int. Volume: 64 Issue: 7 Pages: 299-308
  • DOI: 10.1111/pin.12180
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Epigenetic regulation leading to induced pluripotency drives cancer development in vivo. (2014)
  • Author(s): Ohnishi K, et al.
  • Journal Title: Biochem Biophys Res Commun. Volume: 455 Issue: 1-2 Pages: 10-15
  • DOI: 10.1016/j.bbrc.2014.07.020
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. (2014)
  • Author(s): Ohnishi K, Semi K, Yamamoto T, Shimizu M, Tanaka A, Mitsunaga K, Okita K, Osafune K, Arioka Y, Maeda T, Soejima H, Moriwaki H, Yamanaka S, Woltjen K, Yamada Y.
  • Journal Title: Cell Volume: 156 Issue: 4 Pages: 663-677
  • DOI: 10.1016/j.cell.2014.01.005
  • Peer Reviewed
• [Journal Article] Keratinocyte stem cells but not melanocyte stem cells are the primary target for radiation-induced hair graying. (2013)
  • Author(s): Aoki H
  • Journal Title: J Invest Dermatol Volume: 155 Pages: 600-10
  • DOI: 10.1172/jci63572
  • Peer Reviewed
• [Journal Article] Dose-dependent roles for canonical Wnt signaling in de novocrypt formation and cell cycle properties of the colonic epithelium. (2013)
  • Author(s): Hirata A, et al.
  • Journal Title: Development. Volume: 140(1) Issue: 1 Pages: 66-75
  • DOI: 10.1242/dev.084103
  • Peer Reviewed
• [Journal Article] Cellular reprogramming and cancer development. (2013)
  • Author(s): Semi K, et al.
  • Journal Title: Int J Cancer. Volume: 132(6) Issue: 6 Pages: 1240-1248
  • DOI: 10.1002/ijc.27963
  • Peer Reviewed
• [Journal Article] Activation-induced cytidine deaminase alters the subcellular localization of Tet family proteins. (2012)
  • Author(s): Arioka Y, et al.
  • Journal Title: PLOS One. Volume: 7(9)
  • Peer Reviewed
• [Journal Article] Genetic ablation of Rest leads to in vitro-specific derepression of neuronal genes during neurogenesis (2012)
  • Author(s): Aoki H, Hara A, et al
  • Journal Title: Development Volume: 139 Issue: 4 Pages: 667-677
  • DOI: 10.1242/dev.072272
  • Peer Reviewed
• [Presentation] Dissecting cancer biology by studying induced pluripotency (2014)
  • Author(s): Yasuhiro Yamada
  • Organizer: Nature Conference, Nuclear Reprogramming and the Cancer Genome 2014
  • Place of Presentation: Guangzhou, China
  • Year and Date: 2014-10-31 – 2014-11-02
  • Invited
• [Presentation] Dissecting cancer biology by studying induced pluripotency (2014)
  • Author(s): Yasuhiro Yamada
  • Organizer: 8th International Cell Therapy Conference
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2014-10-23
  • Invited
• [Presentation] Understanding pediatric cancer development by studying induced pluripotency (2014)
  • Author(s): Yasuhiro Yamada
  • Organizer: ADVANCES IN NEUROBLASTOMA RESEARCH
  • Place of Presentation: Colonge, Germany
  • Year and Date: 2014-05-13 – 2014-05-16
  • Invited
• [Presentation] Application of reprogramming technology to cancer research (2013)
  • Author(s): Yasuhiro Yamada
  • Organizer: 19th international Charles Heidelberger symposium on Cancer Research.
  • Place of Presentation: 鹿児島
  • Year and Date: 2013-02-15
• [Presentation] Dissecting cancer biology by studying induced pluripotency.
  • Author(s): Yamada Y
  • Organizer: Gordon Research Conference.
  • Place of Presentation: Galveston, TX, USA
  • Invited