Mechanisms and significance of collective cancer cell migration mediated by cadherin-specific endocytosis

• Project/Area Number: 15H04719
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya University
• Principal Investigator: Enomoto Atsushi 名古屋大学, 医学系研究科, 准教授 (20432255)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 集団的移動 / 集団的浸潤 / 癌 / Girdin / アクチン細胞骨格 / 神経芽細胞 / 細胞間接着 / エンドサイトーシス / 癌の浸潤

Outline of Final Research Achievements

Pathological observations show that cancer cells invade the surrounding stroma in collective groups rather than through single cell migration. We studied the role of the actin-binding protein Girdin in collective cancer cell migration. We found that Girdin was essential for the collective migration of the skin cancer cell line A431 on collagen gels as well as their invasion in an organotypic culture model. We provide evidence that Girdin binds to β-catenin that plays important roles in E-cadherin-mediated cell-cell adhesion. Girdin-depleted cells displayed scattering and impaired cell-cell adhesion. Girdin depletion led to impaired cytoskeletal association of the β-catenin complex, which was accompanied by changes in the supracellular actin cytoskeletal organization. Finally, we showed the significance of Girdin expression in the progression of human skin cancer. Collectively, our results suggest that Girdin is an important modulator of the collective behavior of cancer cells.

Research Products

• [Int'l Joint Research] Central South University(China)
• [Journal Article] Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex (2018)
  • Author(s): Liang Weng , Yi-Peng Han, Atsushi Enomoto, Yasuyuki Kitaura, Shushi Nagamori, Yoshikatsu Kanai, Naoya Asai, Jian An, Maki Takagishi, Masato Asai, Shinji Mii, Takashi Masuko, Yoshiharu Shimomura, Masahide Takahashi.
  • Journal Title: PLoS Biology Volume: 16 Issue: 3 Pages: e2005090-e2005090
  • DOI: 10.1371/journal.pbio.2005090
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ASC amino acid transporter 2, defined by enzyme-mediated activation of radical sources, enhances malignancy of GD2-positive small-cell lung cancer. (2018)
  • Author(s): Nobutoshi Esaki, Yuki Ohkawa, Noboru Hashimoto, Yuhsuke Tsuda, Yuhsuke Ohmi, Robiul H. Bhuiyan, Norihiro Kotani, Koichi Honke, Atsushi Enomoto, Masahide Takahashi, Keiko Furukawa, Koichi Furukawa.
  • Journal Title: Cancer sci. Volume: 109 Issue: 1 Pages: 141-153
  • DOI: 10.1111/cas.13448
  • Peer Reviewed / Open Access
• [Journal Article] Significance of perivascular tumour cells defined by CD109 expression in progression of glioma (2017)
  • Author(s): Shiraki Yukihiro、Mii Shinji、Enomoto Atsushi、Momota Hiroyuki、Han Yi-Peng、Kato Takuya、Ushida Kaori、Kato Akira、Asai Naoya、Murakumo Yoshiki、Aoki Kosuke、Suzuki Hiromichi、Ohka Fumiharu、Wakabayashi Toshihiko、Todo Tomoki、Ogawa Seishi、Natsume Atsushi、Takahashi Masahide
  • Journal Title: The Journal of Pathology Volume: 243 Issue: 4 Pages: 468-480
  • DOI: 10.1002/path.4981
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Daple Coordinates Planar Polarized Microtubule Dynamics in Ependymal Cells and Contributes to Hydrocephalus (2017)
  • Author(s): Maki Takagishi, Masato Sawada, Shinya Ohata, Naoya Asai, Atsushi Enomoto, Kunihiko Takahashi, Liang Weng, Kaori Ushida, Hosne Ara, Shigeyuki Matsui, Kozo Kaibuchi,3Kazunobu Sawamoto, and Masahide Takahashi.
  • Journal Title: Cell Reports Volume: 20 Issue: 4 Pages: 960-972
  • DOI: 10.1016/j.celrep.2017.06.089
  • Peer Reviewed / Open Access
• [Journal Article] Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells. (2017)
  • Author(s): Han YP, Enomoto A, Shiraki Y, Wang SQ, Wang X, Toyokuni S, Asai N, Ushida K, Ara H, Ohka F, Wakabayashi T, Ma J, Natsume A, Takahashi M.
  • Journal Title: Neuro Oncol Volume: 19 Pages: 636-647
  • DOI: 10.1093/neuonc/now237
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High-fat diet feeding promotes stemness and precancerous changes in murine gastric mucosa mediated by leptin receptor signaling pathway (2016)
  • Author(s): Arita S, Kinoshita Y, Ushida K, Enomoto A, Inagaki-Ohara K
  • Journal Title: Arch Biochem Biophys Volume: 610 Pages: 16-24
  • DOI: 10.1016/j.abb.2016.09.015
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Suppression of skin tumorigenesis in CD109-deficient mice. (2016)
  • Author(s): Sunagawa M, Mii S, Enomoto A, Kato T, Murakumo Y, Shiraki Y, Asai N, Asai M, Nagino M, Takahashi M.
  • Journal Title: Oncotarget Volume: 7 Issue: 50 Pages: 82836-82850
  • DOI: 10.18632/oncotarget.12653
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Collective invasion of cancer: Perspectives from pathology and development (2016)
  • Author(s): Wang X, Enomoto A, Asai N, Kato T, Takahashi M
  • Journal Title: Pathol Int Volume: 66 Issue: 4 Pages: 183-192
  • DOI: 10.1111/pin.12391
  • NAID: 120005893271
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of Meflin as a Potential Marker for Mesenchymal Stromal Cells (2016)
  • Author(s): Maeda K, Enomoto A, Hara A, Asai N, Kobayashi T, Horinouchi A, Maruyama S, Ishikawa Y, Nishiyama T, Kiyoi H, Kato T, Ando K, Weng L, Mii S, Asai M, Mizutani Y, Watanabe O, Hirooka Y, Goto H, Takahashi M
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 22288-22288
  • DOI: 10.1038/srep22288
  • Peer Reviewed / Open Access
• [Presentation] Girdin regulates the collective migration of cancer cells by interacting with beta-catenin/alpha-catenin (2017)
  • Author(s): Xiaoze Wang、Atsushi Enomoto、Liang Weng、Naoya Asai、Masahide Takahashi
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 脳腫瘍マウスモデルにおけるテモゾロミド感受性に対するCD109の機能解析 (2017)
  • Author(s): 白木 之浩、三井 伸二、浅井 直也、榎本 篤、百田 洋之、夏目 敦至、若林 俊彦、高橋 雅英
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 病理組織の理解にもとづくがん多様性と進展機序の研究展開 (2017)
  • Author(s): 榎本篤
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
  • Invited
• [Presentation] Mechanisms for the control of amino acid signaling and drug resistance in cancer stem cells (2017)
  • Author(s): 榎本篤、髙橋雅英
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] 間葉系幹細胞およびペリサイトの新規マーカー候補分子Meflinの同定 (2016)
  • Author(s): 前田啓子、榎本篤、後藤秀実、高橋雅英
  • Organizer: 第15回日本再生医療学会総会
  • Place of Presentation: 大阪府・大阪市・大阪国際会議場
  • Year and Date: 2016-03-18
• [Presentation] 脳腫瘍幹細胞におけるmTORC1活性制御とその分子機構の解析 (2016)
  • Author(s): 榎本篤、翁良、韓一梵、浅井直也、三井伸二、高橋雅英
  • Organizer: 日本病理学会秋期特別総会
  • Place of Presentation: 石川県・金沢市・金沢文化ホール
• [Presentation] Meflin is a specific marker for mesenchymal stem cells (MSCs) whose expression is regulated by substrate stiffness (2016)
  • Author(s): Atsushi Enomoto, Naoya Asai, Takeshi Kobayashi, Nobuhisa Nakamura and Masahide Takahashi
  • Organizer: ASCB Annual Meeting 2016
  • Place of Presentation: 米国・サンフランシスコ・モスコーニセンター
  • Int'l Joint Research
• [Presentation] ビメンチンリン酸化不全マウスの皮膚線維芽細胞は染色体異数性を呈し、皮膚の早期老化を示す (2015)
  • Author(s): 田中宏樹、後藤英仁、猪子誠人、牧原弘幸、榎本篤、伊澤一郎、稲垣昌樹
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 愛知県・名古屋市・名古屋国際会議場
  • Year and Date: 2015-10-08