Crosstalk between genomic abnormality and transcription activity for acquisition of stem cell property of cancer

• Project/Area Number: 17K19585
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• 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: Kobayashi Masahiko
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 脳腫瘍 / 幹細胞 / がん幹細胞 / がん

Outline of Final Research Achievements

In this study, we aimed to understand relationship between genomic abnormality and transcription activity for acquisition of stem cell property of brain tumor. We found that primary human astrocytes were immortalized by introducing gene mutations of 4 major tumor suppressors or oncogenes, however, they did not form remarkable tumor mass in vivo, unlike patient-derived glioma samples. In addition, introduction of 4 transcription factors which reportedly contribute to acquisition of stem cell property of differentiated glioma cells were not able to transform immortalized astrocytes into malignant status, indicating that additional mutations are required. In the paralleled experiments, we successfully generated a patient-derived glioma cell clone, in which GFP was inserted at the locus of a stem cell marker gene. Since this GFP system is useful for visualization of stemness of tumor, we expect that it contributes to discovery of factors essential for acquisition of cancer stemness.

Academic Significance and Societal Importance of the Research Achievements

本研究により，がんの幹細胞特性の獲得には多くの因子の異常が複雑に関連していることが明らかとなった。また，本研究で得られた解析ツールを用いることにより，今後，未分化性獲得に必須のシグナルや治療標的を特定することにつながると期待された。本研究を通して得られた成果は，がんの診断，予防，治療の発展に寄与すると考えられ，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

• [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] 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
• [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 (2018)
  • Author(s): Hirao A
  • Organizer: International symposium on drug discovery (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
  • Int'l Joint Research / Invited