A study of microenvironment for maintenance or acquisition of malignant property

• Project/Area Number: 15H02361
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kanazawa 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: ¥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。

Research Products

• [Int'l Joint Research] スタンフォード大学(米国)
• [Journal Article] Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function (2019)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress (2018)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas. (2018)
  • 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: 2497-2508
  • DOI: 10.1111/cas.13695
  • Peer Reviewed / Open Access
• [Journal Article] JLP-JNK signaling protects cancer cells from reactive oxygen species-induced cell death (2018)
  • 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
  • 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 cells (2018)
  • 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
  • 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
  • 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 expression (2017)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug (2017)
  • 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: 111728-111741
  • DOI: 10.18632/oncotarget.22904
  • Peer Reviewed / Open Access
• [Journal Article] MIP-1α/CCL3-expressing basophil-lineage cells drive the leukemic hematopoiesis of chronic myeloid leukemia in mice (2016)
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142 (2015)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] S6 Kinase- and beta-TrCP2-Dependent Degradation of p19Arf Is Required for Cell Proliferation (2015)
  • 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
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Metabolic Regulation of Stemness in Malignant Hematopoiesis (2019)
  • Author(s): Hirao A
  • Organizer: Eleventh AACR-JCA Joint Conference on Breakthroughs in Cancer Research: Biology to Precision Medicine
  • Int'l Joint Research / Invited
• [Presentation] The nutrient signals in self-renewal of hematopoietic stem cells and tumorigenesis (2019)
  • Author(s): Hirao A
  • Organizer: 2019 US-Japan Symposium on Normal/Malignant Hematopoiesis and Novel Therapies for Hematologic Malignancies
  • Int'l Joint Research / Invited
• [Presentation] Metabolic Regulation of Stemness in Malignant Hematopoiesis. International symposium on drug discovery (2018)
  • Author(s): Hirao A
  • Organizer: Joint symposium of Univ. of Tokyo and Novartis Institute
  • Int'l Joint Research / Invited
• [Presentation] Metabolic Control of Cancer Stemness (2018)
  • Author(s): Hirao A
  • Organizer: The 2nd NanoLSI Symposium in London Towards Establishment of New Research Field: Nanoprobe Life Science-
  • Int'l Joint Research / Invited
• [Presentation] Regulation of stem cell properties by metabolic signals in hematopoietic neoplasm (2018)
  • Author(s): Hirao A
  • Organizer: JSPS - National University of Singapore (NUS) 2nd Symposium.
  • 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.
  • 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.
  • 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
  • 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
  • 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
  • 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
  • Int'l Joint Research / Invited
• [Presentation] Stem cell regulation by nutrient signals (2015)
  • 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
  • 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
  • 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
  • Int'l Joint Research / Invited
• [Book] Regulation of Hematopoiesis and Hematological Disease by TGF-b Family Signaling Molecules (2017)
  • Author(s): Naka K., Hirao A
  • Total Pages: 5
  • Publisher: Cold Spring Harbor Laboratory Press
• [Book] Molecular Pathogenesis and Treatment of Chronic Myelogenous leukemia (2015)
  • Author(s): Hirao A, Tadokoro Y, Ueno M
  • Publisher: Springer