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: 平尾 敦 金沢大学, がん進展制御研究所, 教授 (90343350)
• 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 / 栄養 / 幹細胞分化 / 幹細胞

Outline of Annual Research Achievements

本研究では、正常およびがん組織における幹細胞特性を研究対象として、栄養環境シグナルに焦点を当て、オートファジー、mTORなどのシグナル経路の役割とともに、高脂肪食による白血病の発症に関する研究を進めた。まず、オートファジーのがんにおける役割として、脳腫瘍患者由来細胞を用いて解析した結果、Ca濃度を上昇させる化合物によりオートファジーの活性化が認められること、引き続きミトコンドリア傷害が生じること、オートファジー阻害により化合物の感受性が亢進することを見いだした。さらに、同様の機能を有する化合物を探索した結果、新たに複数の中枢神経作動薬を特定した。この結果は、ミトコンドリア機能とオートファジーの関連を示す知見となった。
mTOR関連シグナルとして、前年度から継続してメチオニン関連酵素のがん細胞における役割を解析した。本年度は、関連したシグナルとしてS‐adenosylmethionine（SAM）やS-Adenosyl homocysteine (SAH) を検討した。その結果、少なくとも通常の培養条件では、大きな変動がないことから、予想されるようなヒストンのメチル化の変動による影響ではない可能性が示唆された。また、本分子の白血病以外のがん細胞における役割を解析した結果、免疫不全マウスにおける体内での増殖には必須の役割があることを見いだし、メチオニン以外の経路の重要性が示された。
マウスを用いて、栄養（ダイエット）と白血病幹細胞の関連を解析した結果、高脂肪食による腸内細菌叢の変化によって生じる異常な状態において、RAS-MAPK経路の制御因子であるSpred1の経路が、白血病の抑制分子として機能していることが判明した。本研究によって、白血病発症と腸内細菌叢との関連が明らかとなった。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

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 Sci Alliance. Volume: 2
  • 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 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 Sci. Volume: 109 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: Biochem Biophys Res Commun. Volume: 501 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: Biochem Biophys Res Commun. Volume: 495 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: Sci Rep. Volume: 7 Pages: 1144-1144
  • 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 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] A novel splenic B1 regulatory cell subset suppresses allergic disease through phosphatidylinositol-3-kinase-Akt pathway activation. (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 Pages: 1170-1182
  • DOI: 10.1016/j.jaci.2015.12.1319
  • Peer Reviewed / Acknowledgement Compliant
• [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 Pages: 605-6
  • DOI: 10.1007/s12185-016-2012-4
  • Peer Reviewed
• [Journal Article] The novel oral TGF-β signaling inhibitor EW-7197 eradicates chronic myelogenous leukemia-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 Science Volume: 107 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: Org Lett. Volume: 17 Pages: 5476-5479
  • DOI: 10.1021/acs.orglett.5b02842
  • Peer Reviewed / Open Access
• [Journal Article] S6 Kinase- and β-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: Mol Cell Biol Volume: 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 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