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

Research Project

Project/Area Number 24390096
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Experimental pathology
Research InstitutionKyoto 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 *help
¥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)
KeywordsiPS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 We demonstrate that iPSCs derived from Dox-withdrawn kidney tumor cells give rise to nonneoplastic kidney cells in mice, proving that they have not undergone irreversible genetic transformation.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.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (14 results)

All 2014 2013 2012 Other

All Journal Article (9 results) (of which Peer Reviewed: 9 results,  Acknowledgement Compliant: 3 results) Presentation (5 results) (of which Invited: 4 results)

  • [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

    • Related Report
      2014 Annual Research Report
    • 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

    • Related Report
      2014 Annual Research Report
    • 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

    • Related Report
      2014 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • 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

    • Related Report
      2012 Annual Research Report
    • 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)

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genetic ablation of Rest leads to in vitro-specific derepression of neuronal genes during neurogenesis2012

    • Author(s)
      Aoki H, Hara A, et al
    • Journal Title

      Development

      Volume: 139 Issue: 4 Pages: 667-677

    • DOI

      10.1242/dev.072272

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] Dissecting cancer biology by studying induced pluripotency2014

    • 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
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Dissecting cancer biology by studying induced pluripotency2014

    • Author(s)
      Yasuhiro Yamada
    • Organizer
      8th International Cell Therapy Conference
    • Place of Presentation
      Seoul, Korea
    • Year and Date
      2014-10-23
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Understanding pediatric cancer development by studying induced pluripotency2014

    • Author(s)
      Yasuhiro Yamada
    • Organizer
      ADVANCES IN NEUROBLASTOMA RESEARCH
    • Place of Presentation
      Colonge, Germany
    • Year and Date
      2014-05-13 – 2014-05-16
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Application of reprogramming technology to cancer research2013

    • 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
    • Related Report
      2012 Annual Research Report
  • [Presentation] Dissecting cancer biology by studying induced pluripotency.

    • Author(s)
      Yamada Y
    • Organizer
      Gordon Research Conference.
    • Place of Presentation
      Galveston, TX, USA
    • Related Report
      2013 Annual Research Report
    • Invited

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Published: 2012-04-24   Modified: 2019-07-29  

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