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ストレス応答を介したがん幹細胞ニッチシグナルの解明

Publicly Offered Research

Project AreaDevelopment of Novel Treatment Strategies Targeting Cancer Stem Cells
Project/Area Number 25130705
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKanazawa University

Principal Investigator

平尾 敦  金沢大学, がん進展制御研究所, 教授 (90343350)

Project Period (FY) 2013-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
Fiscal Year 2014: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
Fiscal Year 2013: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
Keywords微小環境 / がん幹細胞
Outline of Annual Research Achievements

本研究では、がんの未分化形質を制御する微小環境シグナルを特定することを目標として、白血病や脳腫瘍細胞に焦点を当てて研究を進めた。昨年に引き続き、脳腫瘍において、高頻度に活性化がみられるmTORシグナルの役割について検討した。活性型EGFRの強制発現とp16/p19欠損の組み合わせにおいて発生する脳腫瘍において、タモキシフェン誘導的にTsc1を欠損させ、in vivoでのmTORC1の更なる活性化を誘導した。その結果、mTORC1の過剰活性化は、スフィア形成細胞能を有する腫瘍細胞の頻度を上昇させた。同時に、大脳基底核への再移植を限界希釈法にて行ったところ、腫瘍発生能を有するいわゆるtumor-initiating cellの頻度は有意に上昇していた。このことから、mTOR活性化が脳腫瘍幹細胞の増幅を誘導するということが判明した。さらに、本実験系において、遺伝子発現解析、蛋白解析、代謝解析を行ったところ、mTORC1の活性化によって、蛋白合成の顕著な亢進とともにミトコンドリアにおける酸化的リン酸化の亢進が認められた。このように、脳腫瘍幹細胞制御にmTORを介したエネルギー代謝制御が重要であることが明らかとなった。また、患者サンプル由来脳腫瘍において、Notch阻害剤の感受性を解析したところ、サンプル間で大きく反応が異なること、感受性を示すサンプルではAKTのリン酸化が低下していること、さらに、CD133やCD44などの幹細胞抗原の発現パターンと有意に相関することが認められた。以上のように、脳腫瘍幹細胞の制御には、微小環境からのmTOR、Notchシグナルが重要な役割を果たしていることが明らかとなった。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (14 results)

All 2015 2014 2013

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 3 results,  Acknowledgement Compliant: 2 results) Presentation (7 results) (of which Invited: 7 results)

  • [Journal Article] Strong therapeutic potential of γ-secretase inhibitor MRK003 for CD44-high and CD133-low glioblastoma initiating cells2015

    • Author(s)
      Tanaka S, Nakada M, Yamada D, Nakano I, Todo T, Ino Y, Hoshii T, Tadokoro Y, Ohta K, Ali MA, Hayashi Y, Hamada J, Hirao A.
    • Journal Title

      J Neurooncol.

      Volume: 121 Issue: 2 Pages: 239

    • DOI

      10.1007/s11060-014-1630-z

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pleiotropic roles of mTOR complexes in haemato-lymphopoiesis and leukemogenesis.2014

    • Author(s)
      Hoshii T, Matsuda S, Hirao A.
    • Journal Title

      J Biochem.

      Volume: 156 Issue: 2 Pages: 73-83

    • DOI

      10.1093/jb/mvu037

    • NAID

      40020155036

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of a murine leukaemia stem cell gene signature based on nucleostemin promoter activity with prognosis of acute myeloid leukaemia in patients.2014

    • Author(s)
      Ali MA, Naka K, Yoshida A, Fuse K, Kasada A, Hoshii T, Tadokoro Y, Ueno M, Ohta K, Kobayashi M, Takahashi C, Hirao A.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 450 Issue: 1 Pages: 837-843

    • DOI

      10.1016/j.bbrc.2014.06.066

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Crosstalk between the RB-pathway and AKT signalling forms a Quiescence-Senescence switch.2014

    • Author(s)
      Imai, Y., Takahashi, A., Hanyuu, A., Hori, S., Sato, S., Naka, K., Hirao, A., Ohtani, N., Hara, E.
    • Journal Title

      Cell Reports

      Volume: 7 Issue: 1 Pages: 194-207

    • DOI

      10.1016/j.celrep.2014.03.006

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Loss of Tsc1 accelerates malignant gliomagenesis when combined with oncogenic signals.2014

    • Author(s)
      Yamada D, Hoshii T, Tanaka S, Hegazy AM, Kobayashi M, Tadokoro Y, Ohta K, Ueno M, Ali MAE, Hirao A.
    • Journal Title

      J Biochem.

      Volume: 155 Issue: 4 Pages: 227-33

    • DOI

      10.1093/jb/mvt112

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells.2013

    • Author(s)
      Hoshii T, Kasada A, Hatakeyama T, Ohtani M, Tadokoro Y, Naka K, Ikenoue T, Ikawa T, Kawamoto H, Fehling HJ, Araki K, Yamamura K, Matsuda S, Hirao A
    • Journal Title

      Proc Natl Acad Sci U S A.

      Volume: 111 Issue: 10 Pages: 3805-3810

    • DOI

      10.1073/pnas.1320265111

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MIP-1α/CCL3-mediated maintenance of leukemia-initiating cells in the initiation process of chronic myeloid leukemia.2013

    • Author(s)
      Baba T, Naka K, Morishita S, Komatsu N, Hirao A, Mukaida N.
    • Journal Title

      J Exp Med.

      Volume: 210 Issue: 12 Pages: 2661-2673

    • DOI

      10.1084/jem.20130112

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] Role of c-Kit signal modulation in the control of self-renewal and aging of hematopoietic stem cells.2015

    • Author(s)
      Hirao A
    • Organizer
      2015 US-Japan meeting on malignant hematopoiesis and stem cells.
    • Place of Presentation
      米国
    • Year and Date
      2015-03-16 – 2015-03-17
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] The signaling pathways for the determination of hematopoietic stem cell fate.2014

    • Author(s)
      平尾 敦
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2014-10-31 – 2014-11-02
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] The nutrient sensing signaling in the cancer stem cells.2014

    • Author(s)
      平尾 敦
    • Organizer
      第73回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] The nutrient sensing signaling pathways in the hematopoietic and leukemia stem cells.2014

    • Author(s)
      Hirao A
    • Organizer
      SNUCRI CANCER SYMPOSIUM
    • Place of Presentation
      韓国
    • Year and Date
      2014-04-16 – 2014-04-19
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] The nutrient sensing signaling pathways in the hematopoietic stem cells and leukemia.2013

    • Author(s)
      Hirao A
    • Organizer
      SUCRI-KUCRI Joint Symposium
    • Place of Presentation
      Seoul National University (Korea)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] The nutrient sensing signaling pathways in the hematopoietic stem cells and leukemia.2013

    • Author(s)
      Hirao A
    • Organizer
      The 23th Hot Spring Harbor International Symposium
    • Place of Presentation
      Kyushu University(Fukuoka)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 栄養センサーシグナルと幹細胞制御2013

    • Author(s)
      平尾敦
    • Organizer
      第86回日本生化学会大会
    • Place of Presentation
      パシフィコ横浜(横浜)
    • Related Report
      2013 Annual Research Report
    • Invited

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Published: 2013-05-15   Modified: 2019-07-29  

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