Molecular mechanisms of cell competition between normal and transformed cells

• Project Area: Cell competition: a mechanism for survival of the fittest in the multi-cellular community
• Project/Area Number: 26114008
• 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: Hokkaido University
• Principal Investigator: Fujita Yasuyuki 北海道大学, 遺伝子病制御研究所, 教授 (50580974)
• Co-Investigator(Kenkyū-buntansha): 伊藤 俊樹 神戸大学, バイオシグナル総合研究センター, 教授 (30313092)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥283,270,000 (Direct Cost: ¥217,900,000、Indirect Cost: ¥65,370,000); Fiscal Year 2018: ¥49,660,000 (Direct Cost: ¥38,200,000、Indirect Cost: ¥11,460,000); Fiscal Year 2017: ¥49,530,000 (Direct Cost: ¥38,100,000、Indirect Cost: ¥11,430,000); Fiscal Year 2016: ¥49,660,000 (Direct Cost: ¥38,200,000、Indirect Cost: ¥11,460,000); Fiscal Year 2015: ¥51,610,000 (Direct Cost: ¥39,700,000、Indirect Cost: ¥11,910,000); Fiscal Year 2014: ¥82,810,000 (Direct Cost: ¥63,700,000、Indirect Cost: ¥19,110,000)
• Keywords: 細胞競合

Outline of Final Research Achievements

The study has been steadily developed, and we have eventually acquired quite satifcatroy achievement.
I will briefly summarized the main publications. 1) Identification of cell competition regulators (Anton et al., 2014, JCS; Ohoka et al., 2015, JCS); 2)Involvement of endocytosis in cell competition (Saitoh et al., 2017, PNAS); 3) Involvement of metabolism in cell competition (Kon et al., 2017, Nat Cell Biol); 4) Cell competition between normal and p53-mutated epithelial cells (Watanabe et al., 2018, Cell Rep); 5) Obesity suppresses apical elimination of RasV12-transformed cells through cell competition (Sasaki et al., 2018, Cell Rep)

Academic Significance and Societal Importance of the Research Achievements

スクリーニングで同定された細胞競合候補分子について、領域班内の様々なモデルシステムを用いて解析を進めることによって、多彩な細胞競合現象を司る普遍的な制御因子の同定を目指す。本研究を精力的に推進することによって今後「周囲の正常細胞に変異細胞を攻撃させる」というがんの社会性を利用した全く新たながん予防・治療戦略の開発へとつなげていく。

Research Products

• [Int'l Joint Research] Oxford University/London Centre for Nanotechnology/University College London(英国)
• [Int'l Joint Research] Grenoble University(フランス)
• [Int'l Joint Research] Oxford University/London Centre for Nanotechnology/University College London(英国)
• [Int'l Joint Research] Grenoble University(フランス)
• [Int'l Joint Research] University of Cardiff/University College London(英国)
• [Int'l Joint Research] University of Bern(スイス)
• [Int'l Joint Research] University College London(英国)
• [Int'l Joint Research] University of Bern(スイス)
• [Journal Article] Obesity Suppresses Cell-Competition-Mediated Apical Elimination of RasV12-Transformed Cells from Epithelial Tissues (2018)
  • Author(s): Sasaki Ayana、Nagatake Takahiro、Egami Riku、Gu Guoqiang、Takigawa Ichigaku、Ikeda Wataru、Nakatani Tomoya、Kunisawa Jun、Fujita Yasuyuki
  • Journal Title: Cell Reports Volume: 23 Issue: 4 Pages: 974-982
  • DOI: 10.1016/j.celrep.2018.03.104
  • NAID: 120006489805
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutant p53-Expressing Cells Undergo Necroptosis via Cell Competition with the Neighboring Normal Epithelial Cells (2018)
  • Author(s): Watanabe Hirotaka、Ishibashi Kojiro、Mano Hiroki、Kitamoto Sho、Sato Nanami、Hoshiba Kazuya、Kato Mugihiko、Matsuzawa Fumihiko、Takeuchi Yasuto、Shirai Takanobu、Ishikawa Susumu、Morioka Yuka、Imagawa Toshiaki、Sakaguchi Kazuyasu、Yonezawa Suguru、Kon Shunsuke、Fujita Yasuyuki
  • Journal Title: Cell Reports Volume: 23 Issue: 13 Pages: 3721-3729
  • DOI: 10.1016/j.celrep.2018.05.081
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ADAM-like Decysin-1 (ADAMDEC1) is a positive regulator of Epithelial Defense Against Cancer (EDAC) that promotes apical extrusion of RasV12-transformed cells (2018)
  • Author(s): Yako Yuta、Hayashi Takashi、Takeuchi Yasuto、Ishibashi Kojiro、Kasai Nobuhiro、Sato Nanami、Kuromiya Keisuke、Ishikawa Susumu、Fujita Yasuyuki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 9639-9639
  • DOI: 10.1038/s41598-018-27469-z
  • NAID: 120006502509
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Accumulation of the myosin-II-spectrin complex plays a positive role in apical extrusion of Src-transformed epithelial cells (2018)
  • Author(s): Mikio Takagi, Masaya Ikegawa, Takashi Shimada, Susumu Ishikawa, Mihoko Kajita, Takeshi Maruyama, Tomoko Kamasaki, Yasuyuki Fujita
  • Journal Title: Genes to Cells Volume: 23 (11) Issue: 11 Pages: 974-981
  • DOI: 10.1111/gtc.12643
  • NAID: 120006734160
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The paxillin-plectin-EPLIN complex promotes apical elimination of RasV12-transformed cells by modulating HDAC6-regulated tubulin acetylation (2018)
  • Author(s): Kasai Nobuhiro、Kadeer Ailijiang、Kajita Mihoko、Saitoh Sayaka、Ishikawa Susumu、Maruyama Takeshi、Fujita Yasuyuki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 2097-2097
  • DOI: 10.1038/s41598-018-20146-1
  • NAID: 120006456414
  • Peer Reviewed / Open Access
• [Journal Article] Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells. (2017)
  • Author(s): S. Saitoh, T. Maruyama, Y. Yako, M. Kajita, Y. Fujioka, Y. Ohba, N. Kasai, N. Sugama, S. Kon, S. Ishikawa, T. Hayashi, T. Yamazaki, M. Tada and Y. Fujita.
  • Journal Title: Proc. Natl. Acad. Sci. U.S.A. Volume: 114 Issue: 12
  • DOI: 10.1073/pnas.1602349114
  • NAID: 120006346108
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes. (2017)
  • Author(s): Shunsuke Kon, et al.
  • Journal Title: Nature Cell Biology Volume: 印刷中 Issue: 5 Pages: 530-541
  • DOI: 10.1038/ncb3509
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell competition in mammals; novel homeostatic machinery for embryonic development and cancer prevention (2017)
  • Author(s): Maruyama Takeshi、Fujita Yasuyuki
  • Journal Title: Current Opinion in Cell Biology Volume: 48 Pages: 106-112
  • DOI: 10.1016/j.ceb.2017.06.007
  • NAID: 120006523718
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Local cellular neighborhood controls proliferation in cell competition (2017)
  • Author(s): Bove Anna、Gradeci Daniel、Fujita Yasuyuki、Banerjee Shiladitya、Charras Guillaume、Lowe Alan R.
  • Journal Title: Molecular Biology of the Cell Volume: 28 Issue: 23 Pages: 3215-3228
  • DOI: 10.1091/mbc.e17-06-0368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plectin is a novel regulator for apical extrusion of RasV12-transformed cells. (2017)
  • Author(s): Kadeer, A., Maruyama, T., Kajita, M., Morita T., Sasaki, A., Ohoka, A., Ishikawa, S., Ikegawa, M., Shimada, T., and Fujita, Y.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 44328-44328
  • DOI: 10.1038/srep44328
  • NAID: 120006219881
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MDCK cells expressing constitutively active Yes-associated protein (YAP) undergo apical extrusion depending on neighboring cell status. (2016)
  • Author(s): Chiba, T., Ishihara, E., Miyamura, N., Narumi, R., Kajita, M., Fujita, Y., Suzuki, A., Ogawa, Y. and *Nishina, H.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 28383-28383
  • DOI: 10.1038/srep28383
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] EphA2 Drives the Segregation of Ras-Transformed Epithelial Cells from Normal Neighbors. (2016)
  • Author(s): Porazinski,S., Navascues, J., Yako, Y., Hill, W., Jones, M.R., Maddison, R., Fujita, Y., and Hogan, C.
  • Journal Title: Current Biology Volume: 5 Issue: 23 Pages: 3220-3229
  • DOI: 10.1016/j.cub.2016.09.037
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A role of the sphingosine-1-phosphate (S1P)- S1P receptor 2 pathway in Epithelial Defense Against Cancer (EDAC) (2015)
  • Author(s): Yamamoto, S., Yako, Y., Fujioka, Y., Kajita, M., Kameyama, T., Kon, S., Ishikawa, S., Ohba, Y., Ohno, Y., Kihara, A., and Fujita, Y.
  • Journal Title: Molecular Biology of the Cell Volume: 27（3） Issue: 3 Pages: 491-499
  • DOI: 10.1091/mbc.e15-03-0161
  • NAID: 120005740332
  • Peer Reviewed / Open Access
• [Journal Article] The cell competition-based high-throughput screening identifies small compounds that promote the elimination of RasV12-transformed cells from epithelia. (2015)
  • Author(s): Yamauchi, H., Matsumaru, T., Morita, T., Ishikawa, S., Maenaka, K., Takigawa, I., Semba, K., Kon, S. and Fujita, Y.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 15336-15336
  • DOI: 10.1038/srep15336
  • NAID: 120005674073
  • Peer Reviewed / Open Access
• [Journal Article] EDAC: Epithelial defence against cancer- cell competition between normal and transformed epithelial cells in mammals. (2015)
  • Author(s): Kajita, M. and Fujita, Y.
  • Journal Title: Journal of Biochemistry Volume: 158(1) Issue: 1 Pages: 15-23
  • DOI: 10.1093/jb/mvv050
  • NAID: 40020522502
  • Peer Reviewed / Open Access
• [Journal Article] EPLIN is a crucial regulator for extrusion of RasV12-transformed cells. (2015)
  • Author(s): Ohoka, A. et al.
  • Journal Title: Journal of Cell Science Volume: 128
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Filamin acts as a key regulator in epithelial defence against transformed cells. (2014)
  • Author(s): Kajita M., Sugimura, K., Ohoka, A., Burden, J., Suganuma, H., Ikegawa, M., Shimada, T., Kitamura, T., Shindoh, M., Ishikawa, S., Yamamoto, S., Saitoh, S., Yako, Y., Takahashi, R., Okajima, T., Kikuta, J., Maijima, Y., Ishii, M., Tada, M., and Fujita, Y.
  • Journal Title: Nature Communications Volume: 5 Issue: 1 Pages: 4428-4428
  • DOI: 10.1038/ncomms5428
  • Peer Reviewed / Open Access
• [Journal Article] PKA-regulated VASP phosphorylation promotes extrusion of transformed cells from the epithelium. (2014)
  • Author(s): Anton, K. A. et al.
  • Journal Title: Journal of Cell Science Volume: 127
  • Peer Reviewed
• [Journal Article] Dynamic and influential interaction of cancer cells with normal epithelial cells in 3D culture. (2014)
  • Author(s): Ivers LP, Cummings B, Owolabi F, Welzel K, Klinger R, Saitoh S, O'Connor D, Fujita Y, Scholz D, Itasaki N.
  • Journal Title: Cancer Cell International Volume: Volume 14 Issue: 1
  • DOI: 10.1186/s12935-014-0108-6
  • Peer Reviewed
• [Presentation] Calcium wave triggers cell extrusion (2018)
  • Author(s): Yasuyuki Fujita
  • Organizer: Gordon Research Conferences, Cell Polarity Signaling
  • Int'l Joint Research / Invited
• [Presentation] 細胞間コミュニケーションの究極の理解を目指して～Cell Competition and Beyond (2018)
  • Author(s): 藤田 恭之
  • Organizer: 第91回日本生化学会
  • Int'l Joint Research / Invited
• [Presentation] 正常上皮細胞と変異細胞に生じる細胞競合 (2018)
  • Author(s): 藤田 恭之
  • Organizer: 第77回日本癌学会学術総会
  • Int'l Joint Research / Invited
• [Presentation] Sequential Oncogene Mutations Profoundly Influence the Outcome of Cell Competition (2018)
  • Author(s): Yasuyuki Fujita
  • Organizer: Cell Competition in Development and Disease
  • Int'l Joint Research / Invited
• [Presentation] 正常上皮細胞と変異細胞に生じる細胞競合 (2018)
  • Author(s): 藤田 恭之
  • Organizer: 第18回日本再生医療学会総会
  • Int'l Joint Research / Invited
• [Presentation] 正常上皮細胞と変異細胞間に生じる細胞競合 (2017)
  • Author(s): 藤田 恭之
  • Organizer: 第16回日本再生医療学会総会
  • Place of Presentation: 仙台国際センター（仙台市）
  • Year and Date: 2017-03-07
  • Int'l Joint Research / Invited
• [Presentation] Cell competition between normal and transformed epithelial cells (2017)
  • Author(s): Yasuyuki Fujita
  • Organizer: The 15th Stem Cell Research Symposium
  • Int'l Joint Research / Invited
• [Presentation] 細胞競合を利用した新規がん予防的治療薬の開発 (2017)
  • Author(s): 藤田 恭之
  • Organizer: 日本ケミカルバイオロジー学会第12回年会
  • Int'l Joint Research / Invited
• [Presentation] Cell competition between Normal and Transformed Epithelial Cells (2017)
  • Author(s): Yasuyuki Fujita
  • Organizer: 24th Asia Pacific Cancer Conference (APCC2017)
  • Int'l Joint Research / Invited
• [Presentation] 細胞競合とワールブルグ効果 (2017)
  • Author(s): 藤田 恭之
  • Organizer: 第42回 日本医用マススペクトル学会年会
  • Int'l Joint Research / Invited
• [Presentation] Cell competition: Cancer-host network in carcinogenesis 細胞競合：発がんにおけるがんー宿主ネットワーク (2017)
  • Author(s): 藤田 恭之
  • Organizer: 第76回日本癌学会学術総会
  • Int'l Joint Research / Invited
• [Presentation] Cell competition between normal and transformed epithelial cells in mammals (2017)
  • Author(s): Yasuyuki Fujita
  • Organizer: CHAMPALIMAUD RESEARCH SYMPOSIUM 2017
  • Int'l Joint Research / Invited
• [Presentation] 細胞競合の分子機構と生理的意義：どこまでわかって何がわからないのか (2017)
  • Author(s): 藤田 恭之
  • Organizer: 2017年度 生命科学系学会合同年次大会
  • Int'l Joint Research / Invited
• [Presentation] Cell competition and Warburg effect」 (2016)
  • Author(s): 藤田 恭之
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-11-30
  • Int'l Joint Research / Invited
• [Presentation] Cell competition and Warburg effect」 (2016)
  • Author(s): 藤田 恭之
  • Organizer: Cell Competition, Apoptosis and Cancer
  • Place of Presentation: Fundacion Ramon Areces, Spain
  • Year and Date: 2016-10-25
  • Int'l Joint Research / Invited
• [Presentation] 細胞競合がもたらすワーブルグ効果様の代謝変化 (2016)
  • Author(s): 藤田 恭之
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-06
  • Int'l Joint Research / Invited
• [Presentation] EDAC(Epitherial Defence Against Cancer) (2016)
  • Author(s): 藤田 恭之
  • Organizer: 第25回日本Cell Death 学会学術集会
  • Place of Presentation: きゅりあん（品川区立総合区民会館）（東京都品川区）
  • Year and Date: 2016-09-10
  • Int'l Joint Research / Invited
• [Presentation] Cell competition in mammalian carcinogenesis (2016)
  • Author(s): 藤田 恭之
  • Organizer: CELL COMPETITION IN FLIES AND MICE in The Allied Genetics Conference 2016
  • Place of Presentation: Orlando World Center Marriott, USA
  • Year and Date: 2016-07-13
  • Int'l Joint Research / Invited
• [Presentation] Competitve interactions between normal and transformed epithelial cells (2015)
  • Author(s): 藤田 恭之
  • 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: 神戸国際会議場（神戸市、兵庫県）
  • Year and Date: 2015-12-01
  • Int'l Joint Research / Invited
• [Presentation] EDAC(Epitherial Defence Against Cancer) (2015)
  • Author(s): 藤田 恭之
  • 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: 2015-10-08
  • Int'l Joint Research / Invited
• [Presentation] Cell Competition and Warburg effect (2015)
  • Author(s): 藤田 恭之
  • Organizer: 第1回国際シンポジウム Cell Competition in Development and Cancer
  • Place of Presentation: 京都大学（京都市、京都府）
  • Year and Date: 2015-09-10
  • Int'l Joint Research
• [Presentation] EDAC(Epitherial Defence Against Cancer) (2015)
  • Author(s): 藤田 恭之
  • Organizer: 第33回日本ヒト細胞学会学術集会
  • Place of Presentation: ホテルスカイタワー（宮崎市、宮崎県）
  • Year and Date: 2015-08-22
  • Invited
• [Presentation] 細胞競合とWarburg effect (2015)
  • Author(s): 藤田 恭之
  • Organizer: 第3回がんと代謝研究会
  • Place of Presentation: 石川県立音楽堂（金沢市、石川県）
  • Year and Date: 2015-07-16
  • Invited
• [Presentation] EDAC(Epitherial Defence Against Cancer) (2015)
  • Author(s): 藤田 恭之
  • Organizer: 第67回日本細胞生物学会
  • Place of Presentation: タワーホール船堀（江戸川区、東京都）
  • Year and Date: 2015-06-29
  • Int'l Joint Research / Invited
• [Presentation] Cell to Cell competition: survival of the fittest as a system of a cellular society (2015)
  • Author(s): 藤田 恭之
  • Organizer: RISK-IR MEETING「Integration and Conceptual Framework Meeting」
  • Place of Presentation: BIOPARK、パリ、フランス
  • Year and Date: 2015-04-27
  • Int'l Joint Research / Invited
• [Presentation] EDAC:Epithelial Defense Against Cancer (2014)
  • Author(s): 藤田 恭之
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] EDAC:Epithelial Defense Against Cancer (2014)
  • Author(s): 藤田 恭之
  • Organizer: Cold Spring Harbor Conference Asia
  • Place of Presentation: 蘇州市、中国
  • Year and Date: 2014-11-17 – 2014-11-21
  • Invited
• [Presentation] Interface between normal and transformed epithlial cells (2014)
  • Author(s): 藤田 恭之
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: グランドプリンスホテル京都（京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] 正常上皮細胞と変異細胞の相互作用-新規がん治療法の確立を目指して- (2014)
  • Author(s): 藤田 恭之
  • Organizer: 第33回 分子病理学研究会～宮城蔵王シンポジウム～
  • Place of Presentation: 宮城蔵王ロイヤルホテル（宮城県刈田郡蔵王町）
  • Year and Date: 2014-07-25 – 2014-07-26
  • Invited
• [Presentation] Interface between normal and transformed epithlial cells - A road to a novel type of cancer treatment - (2014)
  • Author(s): 藤田 恭之
  • Organizer: 国際シンポジウム COMMON MOLECULAR BASIS OF CANCER AND NEURODEGENERATIVE DISEASES, TWO MAJOR HURDLES TO OVERCOME FOR GOOD QUALITY OF LONGEVITY
  • Place of Presentation: 北海道大学（札幌市）
  • Year and Date: 2014-06-27
  • Invited
• [Remarks] 北海道大学 遺伝子病制御研究所 分子腫瘍分野
  • URL: http://www.igm.hokudai.ac.jp/oncology/index.html
• [Remarks] 北海道大学 遺伝子病制御研究所 分子腫瘍分野
  • URL: http://www.igm.hokudai.ac.jp/oncology/index.html
• [Patent(Industrial Property Rights)] トランスジェニック非ヒト哺乳動物及び該動物を用いたがん治療薬のスクリーニング法 (2016)
  • Inventor(s): 藤田 恭之
  • Industrial Property Rights Holder: 藤田 恭之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-054719
  • Filing Date: 2016-03-18