細胞競合を介したがん幹細胞クローン維持機構

• Project Area: Cell competition: a mechanism for survival of the fittest in the multi-cellular community
• Project/Area Number: 15H01487
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kanazawa University
• Principal Investigator: 高橋 智聡 金沢大学, がん進展制御研究所, 教授 (50283619)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: 細胞競合 / RB / 腫瘍内不均一性 / 乳がん / がん抑制遺伝子

Outline of Annual Research Achievements

MCF-7（luminalタイプ乳がん細胞株）とMCF10A（乳腺上皮細胞株）細胞においてモザイク状にRBを不活性化することによって、RB不活性化細胞がそうでない細胞群から細胞競合を受けることが判明した。MCF-7細胞における細胞競合においては、いわゆるapical extrusionののちにRB不活性化細胞は細胞死の表現型を示した。しかし、apical extrusionされるRB不活性化細胞は全体の40%未満であり、完全には駆逐されない。一方、MCF10Aにおける細胞競合では、apical extrusionはRB不活性化細胞の25%程度であったが、apical extrusionに先行して細胞死が起きている可能性が示された。これらの観察は、トランスフォームした細胞群のなかでRBが不活性化する場合と正常細胞群のなかでRBが不活性化する場合とでは、細胞競合の機構が全く異なることを示唆した。Organoid系では、乳腺上皮が内腔側(apical側)で一層となり、筋上皮細胞がそれを取り囲む形態(basal側)が確認された。Bicistronic Cre recombinase-GFPアデノウイルスの感染によって乳腺上皮においてモザイク状にRBが欠失するとき、乳腺上皮が40%ほどの頻度でbasal側に抜け出る現象が観察された。対して、apical側への抜け出しは、5%程度と低かった。すべての乳腺上皮においてRBが欠失するorganoidでは、basal側への抜け出しは、10%程度に抑制されたので、RB欠失細胞が非欠失細胞に取り囲まれる状態が細胞の抜けだしを促進する、つまり、細胞競合的な機序が介在する可能性を見出した。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6. (2017)
  • Author(s): Yoshida A, Kitajima S, Li F, Chaoyang C, Yujiro T, Susumu K, Wan Y, Naoyuki H, Hayato M, Nishimoto Y, Nagatani N, Nishiuchi T, Thai T C, Suzuki S, Nakao S, Tanaka T, Hirose O, Barbie D A and Takahashi C.
  • Journal Title: Oncotarget Volume: 印刷中 Issue: 8 Pages: 13872-85
  • DOI: 10.18632/oncotarget.14681
  • NAID: 120006226780
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Glucoraphanin ameliorates obesity and insulin resistance through adipose tissue browning and reduction of metabolic endotoxemia in mice. (2017)
  • Author(s): Nagata N, Xu L, Kohno S, Ushida Y, Aoki Y, Umeda R, Fuke N, Zhuge F, Ni Y, Nagashimada M, Takahashi C, Suganuma H, Kaneko S and Ota T.
  • Journal Title: Diabetes Volume: 印刷中 Issue: 5 Pages: 1222-1236
  • DOI: 10.2337/db16-0662
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutic strategy for targeting aggressive malignant gliomas by disrupting their energy balance. (2017)
  • Author(s): Hegazy AM, Yamada D, Kobayashi M, Kohno S, Ueno M, Ali MA, Ohta K, Tadokoro Y, Ino Y, Todo T, Soga T, Takahashi C and Hirao A.
  • Journal Title: J Biol Chem Volume: 291 Pages: 21496-21509
  • Peer Reviewed
• [Journal Article] The RB-IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity. (2017)
  • Author(s): Kitajima S, Yoshida A, Susumu K, Li F, Suzuki S, Nagatani N, Nishimoto Y, Sasaki N, Hayato M, Wan Y, Thai T C, Okahashi N, Matsuda F, Shimizu H, Nishiuchi T, Suzuki Y, Tominaga K, Gotoh N, Suzuki M, Ewen M E, Barbie D A, Hirose O, Tanaka T and Takahashi C.
  • Journal Title: Oncogene Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] RB tumor suppressor functions shared by stem cell and cancer cell strategies. (2016)
  • Author(s): Kohno S, Kitajima S, Sasaki N and Takahashi C.
  • Journal Title: World J Stem Cells Volume: 8 Issue: 4 Pages: 170-184
  • DOI: 10.4252/wjsc.v8.i4.170
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Primary Culture of Mouse Thyroid Calcitonin-producing Cell (C cell) Tumors. (2015)
  • Author(s): Kitajima S, Li F, Takahashi C.
  • Journal Title: Bio-Protocol Volume: 5-24
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An in vitro system to characterize prostate cancer progression identified signaling required for self-renewal. (2015)
  • Author(s): Salah M, Nishimoto Y, Kohno S, Kondoh A, Kitajima S, Muranaka H, Nishiuchi T, Ibrahim A, Yoshida A, Takahashi C.
  • Journal Title: Mol Carcinog. Volume: in press Issue: 12 Pages: 1974-1989
  • DOI: 10.1002/mc.22444
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Undifferentiated State Induced by Rb-P53 Double Inactivation in Mouse Thyroid Neuroendocrine Cells and Embryonic Fibroblasts (2015)
  • Author(s): Kitajima S, Kohno S, Kondoh A, Sasaki N, Nishimoto Y, Li F, Mohammed MS, Muranaka H, Nagatani N, Suzuki M, Kido Y, Takahashi C
  • Journal Title: STEM CELLS Volume: - Issue: 5 Pages: 1657-1669
  • DOI: 10.1002/stem.1971
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Metabolic characterization of cultured mammalian cells by mass balance analysis, tracer labeling experiments and computer-aided simulations. (2015)
  • Author(s): Okahashi N, Kohno S, Kitajima S, Matsuda F, Takahashi C, Shimizu H.
  • Journal Title: J Biosci Bioeng. Volume: 120 Issue: 6 Pages: 725-731
  • DOI: 10.1016/j.jbiosc.2015.04.003
  • Peer Reviewed
• [Journal Article] Pleiotropic functions of RB protein in tumor suppression. (2015)
  • Author(s): Hayashi N. and Takahashi C.
  • Journal Title: Archives in Cancer Res Volume: epub
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] RECK-mediated β1-integrin regulation by TGF-β1 is critical for wound contraction in mice. (2015)
  • Author(s): Gutierrez J, Droppelmann CA, Contreras O, Takahashi C and Brandan E.
  • Journal Title: PLoS One Volume: Aug 6 Issue: 8 Pages: e0135005-e0135005
  • DOI: 10.1371/journal.pone.0135005
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 乳腺上皮・乳がんにおけるRBがん抑制遺伝子の不活性化と細胞競合. (2017)
  • Author(s): 西本裕希, Nguyen T K, 髙橋智聡.
  • Organizer: 細胞競合・ダイイングコード合同若手WS
  • Place of Presentation: 大阪市/ホテルコスモスクエア国際交流センター
• [Presentation] がん抑制遺伝子RBによる細胞競合制御 (2016)
  • Author(s): 西本裕希, Nguyen T K, 北嶋俊輔, 髙橋智聡
  • Organizer: 第5回細胞競合コロキウム
  • Place of Presentation: 札幌 北海道大学
  • Year and Date: 2016-03-17
• [Presentation] RB function in controlling glycolysis. (2016)
  • Author(s): Kohno S, Kitajima S and Takahashi C.
  • Organizer: Keystone Symposia
  • Place of Presentation: Banff, Canada/Fairmont Banff Springs
  • Year and Date: 2016-02-24
  • Int'l Joint Research
• [Presentation] Cooperative roles of Rb and SREBP-1 in controlling fatty acid metabolism and carcinogenesis. (2016)
  • Author(s): Muranaka H, Tada H, Hayashi A, Minami K, Kitajima S, Tange S, Suzuki T, Matsuzaka T, Shimano H and Takahashi C
  • Organizer: Keystone Symposia
  • Place of Presentation: Banff, Canada/Fairmont Banff Springs
  • Year and Date: 2016-02-23
  • Int'l Joint Research
• [Presentation] RB tumor suppressor gene regulates cell competition in mammary epithelial cells. (2016)
  • Author(s): Nguyen T K, 西本裕希, 髙橋智聡.
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜/パシフィコ横浜
• [Presentation] NFYAは癌の不均一性構築過程を多段階的に制御する (2016)
  • Author(s): 岡田宣宏, 髙橋智聡
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜/パシフィコ横浜
• [Presentation] The Metabolic Bases for Inflammatory Phenotype Associated with RB-deficiency in Mammary Cells (2016)
  • Author(s): Nishimoto Y, Kitajima S and Takahashi C.
  • Organizer: ourth International Rb Meeting
  • Place of Presentation: Hilton Columbus Downtown /コロンバス オハイオ州
  • Int'l Joint Research
• [Presentation] インビトロがん幹細胞モデルの細胞競合研究への応用 (2015)
  • Author(s): 西本裕希, 北嶋俊輔, 河野晋, 髙橋智聡
  • Organizer: 第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸 神戸ポートアイランド
  • Year and Date: 2015-12-02
  • Int'l Joint Research
• [Presentation] RBがん抑制遺伝子による代謝制御 (2015)
  • Author(s): 髙橋智聡
  • Organizer: 第46回高松宮妃癌研究基金国際シンポジウム
  • Place of Presentation: 東京 パレスホテル東京
  • Year and Date: 2015-11-17
  • Int'l Joint Research / Invited
• [Presentation] Cooperative roles of Rb and SREBP-1 in controlling fatty acid metabolism and carcinogenesis. (2015)
  • Author(s): Muranaka H, Tada H, Hayashi A, Minami K, Kitajima S, Tange S, Suzuki T, Matsuzaka T, Shimano H, Takahashi C.
  • Organizer: Cancer and Metabolism conference
  • Place of Presentation: 英国 Cambridge/Robinson College
  • Year and Date: 2015-09-29
  • Int'l Joint Research
• [Presentation] The interface between tumor cells with different RB status and self-renewal activity. (2015)
  • Author(s): 髙橋智聡
  • Organizer: 1st International Symposium on Cell Competition / Cell Competition in Development and Cancer.
  • Place of Presentation: 京都 京都大学 芝欄会館
  • Year and Date: 2015-09-10
  • Int'l Joint Research
• [Presentation] RB1不活性化シグナチャー解析による新規分子標的探索 (2015)
  • Author(s): 髙橋智聡
  • Organizer: 第19回日本がん分子標的治療学会学術集会
  • Place of Presentation: 松山 松山全日空ホテル
  • Year and Date: 2015-06-11
  • Invited
• [Presentation] Metabolic functions of RB tumor suppressor in controlling undifferentiated state. (2015)
  • Author(s): Takahashi C
  • Organizer: 2015 the Catholic Univ. of Korea Seoul St Mary’s Hospital Comprehensive Cancer Institute International Symposium
  • Place of Presentation: 韓国 ソウル St Mary’s Hospital
  • Year and Date: 2015-05-22
  • Int'l Joint Research / Invited
• [Book] 生体の科学 特集『細胞の社会学―細胞間で繰り広げられる協調と競争』「13．がん細胞社会のなかの多様性・多層性」 (2016)
  • Author(s): 西本裕希、髙橋智聡
  • Total Pages: 4
  • Publisher: 医学書院刊
• [Book] 生体の科学 がん細胞の中の多様性・多層性 (2016)
  • Author(s): 西本裕希、高橋智聡
  • Publisher: 医学書院
• [Book] マウス甲状腺C細胞および線維芽細胞は高度な未分化性を獲得する. BioMedサーカス.com 最新研究情報「執筆者自身による研究論文レビュー 第35回」 (2015)
  • Author(s): 北嶋俊輔, 河野晋, 髙橋智聡
  • Publisher: BioMedサーカス.com
• [Book] 家族性腫瘍学 ― 家族性腫瘍の最新研究動向 ― II. 各論 原因遺伝子 RB1. 日本臨牀 (2015)
  • Author(s): 髙橋智聡
  • Publisher: 日本臨牀
• [Remarks] 髙橋智聡研究室HP
  • URL: http://omb.w3.kanazawa-u.ac.jp/index.html
• [Remarks] がん進展制御研究所HP
  • URL: http://ganken.cri.kanazawa-u.ac.jp
• [Remarks] 高橋智聡研究室HP
  • URL: http://omb.w3.kanazawa-u.ac.jp
• [Remarks] 金沢大学がん進展制御研究所HP
  • URL: http://ganken.cri.kanazawa-u.ac.jp