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The role of metabolic and epigenetic heterogeneity in glioblastoma treatment

Research Project

Project/Area Number 15K19067
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Human pathology
Research InstitutionTokyo Women's Medical University

Principal Investigator

Masui Kenta  東京女子医科大学, 医学部, 助教 (60747682)

Research Collaborator MISCHEL Paul  
Project Period (FY) 2015-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords悪性脳腫瘍 / Heterogeneity / mTORC2 / がん代謝 / エピジェネティクス / ヒストンアセチル化 / テロメア / がん幹細胞 / 組織内不均一性
Outline of Final Research Achievements

Intratumoral heterogeneity generates subpopulations of cancer cells with distinct genotypes and phenotypes, but the mechanisms how oncogenic signaling establishes functional heterogeneity remain to be elucidated. Here, we identify an unexpected central role for mTORC2 in creating epigenetic heterogeneity where it controls diverse histone acetylation by dynamically reprogramming intracellular metabolism. We show that mTORC2 promotes the production of acetyl-CoA as well as the subcellular translocation of histone modifying enzymes, and this in turn facilitates the transcription of telomerase components via histone acetylation at the promoter regions. These central features of activated mTORC2 signaling, acetylated histone marks and telomerase expression are inter-correlated in clinical samples, and maintain telomere length and self-renewal capacity in glioblastoma cells. These results identify a specific role for mTORC2 in regulating functional heterogeneity in cancer epigenetics.

Report

(3 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • Research Products

    (12 results)

All 2017 2016 2015

All Journal Article (4 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 3 results,  Acknowledgement Compliant: 3 results) Presentation (8 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Heterogeneityとがんの治療抵抗性2017

    • Author(s)
      増井 憲太
    • Journal Title

      月刊細胞

      Volume: 49 Pages: 47-51

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Cancer metabolism as a central driving force of glioma pathogenesis2016

    • Author(s)
      Masui K, Cavenee WK, Mischel PS
    • Journal Title

      Brain Tumor Pathology

      Volume: 33 Issue: 3 Pages: 161-168

    • DOI

      10.1007/s10014-016-0265-5

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] mTORC2 activity in brain cancer: Extracellular nutrients are required to maintain oncogenic signaling2016

    • Author(s)
      Masui K, Shibata N, Cavenee WK, Mischel PS
    • Journal Title

      Bioessays

      Volume: 38 Issue: 9 Pages: 839-844

    • DOI

      10.1002/bies.201600026

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] mTORC2 and Metabolic Reprogramming in GBM: at the Interface of Genetics and Environment2015

    • Author(s)
      Masui K, Cavenee WK, Mischel PS
    • Journal Title

      Brain Pathology

      Volume: 25 Issue: 6 Pages: 755-759

    • DOI

      10.1111/bpa.12307

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] mTORC2 promotes histone acetylation through metabolic reprogramming in glioblastoma2016

    • Author(s)
      Kenta Masui, Paul S. Mischel, Noriyuki Shibata
    • Organizer
      The 13th Asian Society for Neuro-Oncology
    • Place of Presentation
      シドニー(オーストラリア)
    • Year and Date
      2016-09-11
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 悪性脳腫瘍の病態に関わる蛋白翻訳後修飾2016

    • Author(s)
      増井憲太, Webster K. Cavenee, Paul S. Mischel, 柴田亮行
    • Organizer
      第4回がんと代謝研究会
    • Place of Presentation
      かごしま県民交流センター(鹿児島県鹿児島市)
    • Year and Date
      2016-07-07
    • Related Report
      2016 Annual Research Report
  • [Presentation] 悪性脳腫瘍細胞の増殖と生存に蛋白の翻訳後修飾が関与する2016

    • Author(s)
      増井憲太, Paul S. Mischel, 柴田亮行
    • Organizer
      第57回日本神経病理学会総会学術研究会
    • Place of Presentation
      ホテルニューキャッスル(青森県弘前市)
    • Year and Date
      2016-06-01
    • Related Report
      2016 Annual Research Report
  • [Presentation] がん細胞においてmTORC2は代謝系リプログラミングを介してヒストンのアセチル化を促進する2016

    • Author(s)
      増井憲太, Paul S. Mischel, 柴田亮行
    • Organizer
      第105回日本病理学会総会
    • Place of Presentation
      仙台国際センター(宮城県仙台市)
    • Year and Date
      2016-05-12
    • Related Report
      2016 Annual Research Report
  • [Presentation] GLUCOSE-DEPENDENT MECHANISM OF TARGETED CANCER THERAPY RESISTANCE2016

    • Author(s)
      Kenta Masui, Paul Mischel, Noriyuki Shibata
    • Organizer
      The 21st International Conference on Brain Tumor Research and Therapy
    • Place of Presentation
      万国津梁館(沖縄県名護市)
    • Year and Date
      2016-04-10
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 膠芽腫はグルコース代謝を利用して標的治療抵抗性を獲得する2015

    • Author(s)
      増井憲太、Cavenee Webster、Mischel Paul、柴田亮行
    • Organizer
      第33回日本脳腫瘍学会
    • Place of Presentation
      グランドプリンスホテル京都(京都府京都市)
    • Year and Date
      2015-12-06
    • Related Report
      2015 Research-status Report
  • [Presentation] 悪性脳腫瘍はグルコースの代謝を介して治療抵抗性を獲得する2015

    • Author(s)
      増井憲太、ポール・ミシェル、柴田亮行
    • Organizer
      第10回臨床ストレス応答学会
    • Place of Presentation
      東京農工大学140周年記念会館(東京都小金井市)
    • Year and Date
      2015-11-06
    • Related Report
      2015 Research-status Report
  • [Presentation] がん代謝による標的治療抵抗性機序の解明2015

    • Author(s)
      増井憲太, Webster K. Cavenee, Paul S. Mischel
    • Organizer
      第3回がんと代謝研究会
    • Place of Presentation
      石川県立音楽堂(石川県金沢市)
    • Year and Date
      2015-07-16
    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2018-03-22  

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