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A study of microenvironment for maintenance or acquisition of malignant property

Research Project

Project/Area Number 15H02361
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor biology
Research InstitutionKanazawa University

Principal Investigator

HIRAO Atsushi  金沢大学, がん進展制御研究所, 教授 (90343350)

Research Collaborator Tadokoro Yuko  
Kobayashi Masahiko  
Ueno Masaya  
Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥42,770,000 (Direct Cost: ¥32,900,000、Indirect Cost: ¥9,870,000)
Fiscal Year 2018: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2017: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2016: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2015: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
Keywordsがん / 幹細胞 / 栄養 / 幹細胞分化
Outline of Final Research Achievements

In this study, we aimed to understand molecular mechanisms of malignant property in aspect of stem cell regulation by nutrient signals. As a result, firstly, we found that activation of mTOR complex 1 induces upregulation of glycolysis and mitochondrial activity and contributes to good balance between energy consumption and production for tumor progression. Secondly, we revealed that combining a Ca2+ mobilizer with the autophagy inhibitor remarkably suppress tumor growth in vitro and in vivo, proposing new therapeutics for GBM patients. Thirdly, we discovered an important tumor suppressive mechanism in hematopoietic stem cells against the ill effects caused by the dysbiosis (microbial imbalance) of gut microbiota induced by a high fat diet.

Academic Significance and Societal Importance of the Research Achievements

本研究では,日常的な栄養環境がどのように,がんの発生や悪性化に寄与しているのかという疑問に対し,分子レベルでの制御機構の理解を進めた。その結果,新たな治療標的分子の発見やがんの発症の予防に寄与できる複数の研究成果を得ることができた。本研究を通して得られた成果は,将来,健康福祉の観点から社会に貢献することが期待される。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (32 results)

All 2019 2018 2017 2016 2015 Other

All Int'l Joint Research (1 results) Journal Article (15 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 15 results,  Open Access: 8 results,  Acknowledgement Compliant: 2 results) Presentation (14 results) (of which Int'l Joint Research: 13 results,  Invited: 14 results) Book (2 results)

  • [Int'l Joint Research] スタンフォード大学(米国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function2019

    • Author(s)
      Imanishi Takayuki、Unno Midori、Kobayashi Wakana、Yoneda Natsumi、Matsuda Satoshi、Ikeda Kazutaka、Hoshii Takayuki、Hirao Atsushi、Miyake Kensuke、Barber Glen N、Arita Makoto、Ishii Ken J、Akira Shizuo、Saito Takashi
    • Journal Title

      Life Science Alliance

      Volume: 2 Issue: 1 Pages: e201800282-e201800282

    • DOI

      10.26508/lsa.201800282

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress2018

    • Author(s)
      Tadokoro Yuko、Hoshii Takayuki、Yamazaki Satoshi、Eto Koji、Ema Hideo、Kobayashi Masahiko、Ueno Masaya、Ohta Kumiko、Arai Yuriko、Hara Eiji、Harada Kenichi、Oshima Masanobu、Oshima Hiroko、Arai Fumio、Yoshimura Akihiko、Nakauchi Hiromitsu、Hirao Atsushi
    • Journal Title

      Cell Stem Cell

      Volume: 22 Issue: 5 Pages: 713-725

    • DOI

      10.1016/j.stem.2018.04.002

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas2018

    • Author(s)
      Vu HT, Kobayashi M, Hegazy AM, Tadokoro Y, Ueno M, Kasahara A, Takase Y, Nomura N, Peng H, Ito C, Ino Y, Todo T, Nakada M, Hirao A
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 8 Pages: 2497

    • DOI

      10.1111/cas.13695

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] JLP-JNK signaling protects cancer cells from reactive oxygen species-induced cell death2018

    • Author(s)
      Li Rong、Gunarta I. Ketut、Suzuki Ryusuke、Boldbaatar Jambaldorj、Nakazato Ryota、Yuliana Dewi、Davaakhuu Gantulga、Oyunsuren Tsendsuren、Takamatsu Nobuhiko、Kobayashi Masahiko、Hirao Atsushi、Yoshioka Katsuji
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 501 Issue: 3 Pages: 724-730

    • DOI

      10.1016/j.bbrc.2018.05.055

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells2018

    • Author(s)
      Hui Peng, Atsuo Kasada, Masaya Ueno, Takayuki Hoshii, Yuko Tadokoro, Naho Nomura, Chiaki Ito, Yusuke Takase, Ha Thi Vu, Masahiko Kobayashi, Bo Xiao, Paul F. Worley, Atsushi Hirao
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 495 Issue: 1 Pages: 1129-1135

    • DOI

      10.1016/j.bbrc.2017.11.140

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Spred1 safeguards hematopoietic homeostasis against diet-induced systemic stress.2018

    • Author(s)
      Tadokoro Y, Hoshii T, Yamazaki S, Eto K, Ema H, Kobayashi M Ueno M, Ohta K, Arai Y, Hara E, Harada K, Oshima M, Oshima H, Arai F, Yoshimura A, Nakauchi N, Hirao A.
    • Journal Title

      Cell Stem Cell

      Volume: 印刷中

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Functional dissection of hematopoietic stem cell populations with a stemness-monitoring system based on NS-GFP transgene expression2017

    • Author(s)
      Ali Mohamed A. E.、Fuse Kyoko、Tadokoro Yuko、Hoshii Takayuki、Ueno Masaya、Kobayashi Masahiko、Nomura Naho、Vu Ha Thi、Peng Hui、Hegazy Ahmed M.、Masuko Masayoshi、Sone Hirohito、Arai Fumio、Tajima Atsushi、Hirao Atsushi
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 11442-11442

    • DOI

      10.1038/s41598-017-11909-3

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug2017

    • Author(s)
      Dong Y, Furuta T, Sabit H, Kitabayashi T, Jiapaer S, Kobayashi M, Ino Y, Todo T, Teng L, Hirao A, Zhao SG, Nakada M
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 67 Pages: 111728

    • DOI

      10.18632/oncotarget.22904

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MIP-1α/CCL3-expressing basophil-lineage cells drive the leukemic hematopoiesis of chronic myeloid leukemia in mice2016

    • Author(s)
      Baba T, Tanabe Y, Yoshikawa S, Yamanishi Y, Morishita S, Komatsu N, Karasuyama H, Hirao A, Mukaida N.
    • Journal Title

      Blood

      Volume: 127 Pages: 2607-17

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The PI3K-Akt pathway controls IL-10-producing regulatory B cells.2016

    • Author(s)
      MatsushitaT, Huu DL, Hamaguchi Y, Hasegawa M, Naka K, Hirao A, Muramatsu M, Takehara K, Fujimoto M.
    • Journal Title

      J Allergy Clin Immunol

      Volume: 印刷中 Issue: 4 Pages: 21496-21509

    • DOI

      10.1016/j.jaci.2015.12.1319

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cooperative networks for stem cell homeostasis in normal and malignant hematopoiesis: from metabolism to epigenetics.2016

    • Author(s)
      Hirao A.
    • Journal Title

      Int J Hematol

      Volume: 103 Issue: 6 Pages: 605-6

    • DOI

      10.1007/s12185-016-2012-4

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells.2016

    • Author(s)
      Naka K, Ishihara K, Jomen Y, Jin CH, Kim DH, Gu YK, Jeong ES, Li S, Krause DS, Kim DW, Bae E, Takihara Y, Hirao A, Oshima H, Oshima M, Ooshima A, Sheen YY, Kim SJ, Kim DK.
    • Journal Title

      Cancer Sci.

      Volume: 107 Issue: 2 Pages: 140-148

    • DOI

      10.1111/cas.12849

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-1422015

    • Author(s)
      Teppei Kawahara, Noritaka Kagaya, Yuichi Masuda, Takayuki Doi, Miho Izumikawa, Kumiko Ohta, Atsushi Hirao, Kazuo Shin-ya
    • Journal Title

      Organic letters

      Volume: 17 Issue: 21 Pages: 5476-5479

    • DOI

      10.1021/acs.orglett.5b02842

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] S6 Kinase- and beta-TrCP2-Dependent Degradation of p19Arf Is Required for Cell Proliferation2015

    • Author(s)
      Nakagawa T, Araki T, Nakagawa M, Hirao A, Unno M, Nakayama K
    • Journal Title

      Molecular and cellular biology

      Volume: 20 Issue: 20 Pages: 3517-3527

    • DOI

      10.1128/mcb.00343-15

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism.2015

    • Author(s)
      .Fahkri H, Zhang B, Fajol A, Hernando N, Elvira B, Mannheim JG, Pichler BJ, Daniel C, Amann K, Hirao A, Haight J, Mak TW, Lang F, Föller M.
    • Journal Title

      Pflugers Arch.

      Volume: 467 Issue: 9 Pages: 1871-1880

    • DOI

      10.1007/s00424-014-1625-9

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Metabolic Regulation of Stemness in Malignant Hematopoiesis2019

    • Author(s)
      Hirao A
    • Organizer
      Eleventh AACR-JCA Joint Conference on Breakthroughs in Cancer Research: Biology to Precision Medicine
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The nutrient signals in self-renewal of hematopoietic stem cells and tumorigenesis2019

    • Author(s)
      Hirao A
    • Organizer
      2019 US-Japan Symposium on Normal/Malignant Hematopoiesis and Novel Therapies for Hematologic Malignancies
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Metabolic Regulation of Stemness in Malignant Hematopoiesis. International symposium on drug discovery2018

    • Author(s)
      Hirao A
    • Organizer
      Joint symposium of Univ. of Tokyo and Novartis Institute
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Metabolic Control of Cancer Stemness2018

    • Author(s)
      Hirao A
    • Organizer
      The 2nd NanoLSI Symposium in London Towards Establishment of New Research Field: Nanoprobe Life Science-
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulation of stem cell properties by metabolic signals in hematopoietic neoplasm2018

    • Author(s)
      Hirao A
    • Organizer
      JSPS - National University of Singapore (NUS) 2nd Symposium.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Hematopoietic stem cell homeostasis under diet-induced systemic stress.2017

    • Author(s)
      Hirao A
    • Organizer
      The joint symposium on tumor microenvironemnt and precision medicine.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulation of stem cell properties by nutrient signals in hematopoietic neoplasms.2017

    • Author(s)
      Hirao A
    • Organizer
      2017 Cancer Biology Symposium.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 造血幹細胞の運命決定機構ー自己複製の異常と疾患ー2017

    • Author(s)
      平尾敦
    • Organizer
      第7回細胞再生医療学会
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 栄養シグナルと幹細胞制御2016

    • Author(s)
      平尾敦
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-12-01
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular mechanism regulating stem cell properties mediated by nutrient signals.2016

    • Author(s)
      Hirao A
    • Organizer
      46th International Symposium of the Princess Takamatsu Cancer Research Fund
    • Place of Presentation
      Tokyo
    • Year and Date
      2016-11-07
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular mechanism linking hematopoietic stem cell aging and leukemogenesis.2016

    • Author(s)
      Hirao A
    • Organizer
      Fifth JCA-AACR Special Joint Conference on the Latest Advances in Hematological Cancer Research
    • Place of Presentation
      Urayasu, Chiba
    • Year and Date
      2016-07-13
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Stem cell regulation by nutrient signals2015

    • Author(s)
      Hirao A
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋国際会議場(名古屋市、愛知県)
    • Year and Date
      2015-10-09
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Molecular mechanism linking between hematopoietic stem cell aging and leukemogenesis.2015

    • Author(s)
      Hirao A
    • Organizer
      International Society for Experimental Hematology(ISEH) 44th Annual Scientific Meeting
    • Place of Presentation
      京都国際会議場(京都市、京都府)
    • Year and Date
      2015-09-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Role of nutrient sensing signaling pathways in the maintenance of leukemia stem cells.2015

    • Author(s)
      Hirao A
    • Organizer
      SNUCRI CANCER SYMPOSIUM
    • Place of Presentation
      Kumho Hwasun Resort(Hwasun, Korea)
    • Year and Date
      2015-04-03
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Book] Regulation of Hematopoiesis and Hematological Disease by TGF-b Family Signaling Molecules2017

    • Author(s)
      Naka K., Hirao A
    • Total Pages
      5
    • Publisher
      Cold Spring Harbor Laboratory Press
    • Related Report
      2016 Annual Research Report
  • [Book] Molecular Pathogenesis and Treatment of Chronic Myelogenous leukemia2015

    • Author(s)
      Hirao A, Tadokoro Y, Ueno M
    • Publisher
      Springer
    • Related Report
      2015 Annual Research Report

URL: 

Published: 2015-04-16   Modified: 2020-03-30  

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