Molecular mechanisms of EDAC (Epithelial Defense Against Cancer)

• Project/Area Number: 26250026
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• 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)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥40,430,000 (Direct Cost: ¥31,100,000、Indirect Cost: ¥9,330,000); Fiscal Year 2017: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2016: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2015: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2014: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000)
• Keywords: 細胞競合

Outline of Final Research Achievements

In this study, we have identified molecules that are involved in EDAC (epithelial defense against cancer) whereby transformed cells are eliminated from epithelia via cell competition with the surrounding normal epithelial cells. First, we have found that expression of a soluble factor ADAMDEC1 is non-cell-autonomously upregulated in normal cells neighboring transformed cells, which positively regulate apical extrusion of transformed cells. In addition, we also demonstrate that expression of COX-2 is increased in normal cells surrounding transformed cells, which induces inflammatory responses thereby negatively regulating cell competition. Collectively, these results indicate the presence of both negative and positive regulators of cell competition.

Research Products

• [Int'l Joint Research] University College London(英国)
• [Int'l Joint Research] Swiss Institute of Technology Lausanne(スイス)
• [Int'l Joint Research] University College London/Cardiff University(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] 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] 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 A、Gradeci D、Fujita Y、Banerjee S、Charras G、Lowe AR
  • Journal Title: Molecular Biology of the Cell Volume: 28 Pages: 3215-3228
  • Peer Reviewed / Open Access
• [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] 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] 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., Kajita, M., Ikenouchi, J., Yako, Y., Kitamoto, S., Kon, S., Ikegawa, M., Shimada, T., Ishikawa, S., and Fujita, Y.
  • Journal Title: Journal of Cell Science Volume: 128 Pages: 781-789
  • DOI: 10.1242/jcs.163113
  • 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 Pages: 3425-3433
  • DOI: 10.1242/jcs.149674
  • 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] 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): 藤田 恭之
  • Organizer: The 15th Stem Cell Research Symposium
  • 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
  • Invited
• [Presentation] Cell competition between Normal and Transformed Epithelial Cells (2017)
  • Author(s): 藤田 恭之
  • Organizer: 24th Asia Pacific Cancer Conference (APCC2017)
  • Int'l Joint Research / Invited
• [Presentation] 細胞競合とWarburg effect (2017)
  • Author(s): 藤田 恭之
  • Organizer: 第6回がんと代謝研究会
  • 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
  • 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): 藤田 恭之
  • Organizer: CHAMPALIMAUD RESEARCH SYMPOSIUM 2017
  • Int'l Joint Research / Invited
• [Presentation] Cell Cimpetition between normal and trandformed epithelial cells (2017)
  • Author(s): 藤田 恭之
  • Organizer: 12th International Symposium of the Institute Network
  • 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
• [Presentation] 正常上皮細胞と変異細胞の相互作用 (2014)
  • Author(s): 藤田 恭之
  • Organizer: 第79回 インターフェロン・サイトカイン学会学術集会
  • Place of Presentation: 北海道大学（札幌市）
  • Year and Date: 2014-06-19
  • Invited
• [Remarks] 北海道大学 遺伝子病制御研究所 分子腫瘍分野のホームページ
  • 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方法 (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