Integrated understanding of intercellular communication and contraction forces

• Project/Area Number: 20K21411
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: Kyoto University
• Principal Investigator: Fujita Yasuyuki 京都大学, 医学研究科, 教授 (50580974)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 細胞競合 / 収縮力 / 牽引力顕微鏡 / カルシウムスパーク / TRPC1 / 細胞内カルシウム / 細胞間コミュニケーション

Outline of Research at the Start

物理学と生物学の融合については、世界的に様々な試みがなされてきた。例えば、メカノバイオロジーでは力学を、神経生理学では電気物理学を生物学に取り込むことによって新たな研究分野を創出してきた。一方、波動物理学と生物学の融合については、未開拓のまま残されている。本研究は、新たに見出された波動様収縮力と細胞間コミュニケーションの関わりをターゲットとしている。「波動が細胞間のコミュニケーションにも関わっているのではないか」というアイデアは世界的にも例を見ない斬新性、新規性の高いものあり、『波動生物学』という新たな研究分野の創出につながりえる、挑戦的研究にふさわしい研究構想になっている。

Outline of Final Research Achievements

When an oncogenic mutation occurs within a monolayer of epithelial cells, cell competition occurs between normal and the newly emerging transformed cells. However, the molecular mechanisms of cell competition still remain largely unknown.
In this study, we have demonstrated that a transient upsurge of intracellular calcium occurs in normal cells neighboring transformed cells, which is termed ‘calcium spark’. In addition, by analyzing various physical parameters, we have found that compressive forces are imposed onto normal cells neighboring transformed cells, which induces the increased membrane tension. The increased membrane tension then leads to the occurrence of calcium sparks mediated by mechano-sensitive calcium channel.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、変異細胞に隣接した正常細胞では、様々な物理的、化学的な変化が生じ、その結果、変異細胞の上皮細胞層からの排除を促進していることが明らかになった。これまで、細胞競合における細胞の物理的な変化については、ほとんど報告がなく、細胞競合研究分野に新たな見地を与える研究成果であると高く評価できる。また、これらのデータは、これまでブラックボックスであったがんの超初期段階で起こるプロセスの一端を明らかにするものであり、今後のがんの予防的治療薬の開発にもつながり得る研究成果であると言えよう。

Research Products

• [Journal Article] The CD44/COL17A1 Pathway Plays a Vital Role in the Formation of Multilayered, Transformed Epithelia. (2021)
  • Author(s): Kozawa K, ,Sekai M, Ohba K, Ito S, Sako H, Maruyama T, Kakeno M , Kuromiya K, Kamasaki T, Kohashi K, Ishikawa S, Sato N, Asano S, Suzuki H, Tanimura N, Mukai Y, Gotoh N, Tanino M, Tanaka S Natsuga K, Soga T. Nakamura T, Yabuta Y, Saitou M, Ito T, Matsuura K, Tsunoda M,et.al..
  • Journal Title: Curr Biol Volume: 31 Issue: 14 Pages: 3086-3097
  • DOI: 10.1016/j.cub.2021.04.078
  • Peer Reviewed / Open Access
• [Journal Article] Sequential oncogenic mutations influence cell competition (2021)
  • Author(s): Kohashi Koki、Mori Yusuke、Narumi Rika、Kozawa Kei、Kamasaki Tomoko、Ishikawa Susumu、Kajita Mihoko、Kobayashi Rei、Tamori Yoichiro、Fujita Yasuyuki
  • Journal Title: Current Biology Volume: 31 Issue: 18 Pages: 3984-3995
  • DOI: 10.1016/j.cub.2021.06.064
  • Peer Reviewed / Open Access
• [Journal Article] Cell competition-induced apical elimination of transformed cells, EDAC, orchestrates the cellular homeostasis (2021)
  • Author(s): Kon Shunsuke、Fujita Yasuyuki
  • Journal Title: Developmental Biology Volume: 476 Pages: 112-116
  • DOI: 10.1016/j.ydbio.2021.03.015
  • Peer Reviewed / Open Access
• [Journal Article] FBP17-mediated finger-like membrane protrusions in cell competition between normal and RasV12-transformed cells (2021)
  • Author(s): Kamasaki Tomoko、Miyazaki Yumi、Ishikawa Susumu、Hoshiba Kazuya、Kuromiya Keisuke、Tanimura Nobuyuki、Mori Yusuke、Tsutsumi Motosuke、Nemoto Tomomi、Uehara Ryota、Suetsugu Shiro、Itoh Toshiki、Fujita Yasuyuki
  • Journal Title: iScience Volume: 24 Issue: 9 Pages: 102994-102994
  • DOI: 10.1016/j.isci.2021.102994
  • Peer Reviewed / Open Access
• [Journal Article] Homeostatic membrane tension constrains cancer cell dissemination by counteracting BAR protein assembly (2021)
  • Author(s): Tsujita Kazuya、Satow Reiko、Asada Shinobu、Nakamura Yoshikazu、Arnes Luis、Sako Keisuke、Fujita Yasuyuki、Fukami Kiyoko、Itoh Toshiki
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 5930-5930
  • DOI: 10.1038/s41467-021-26156-4
  • NAID: 120007165701
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FGF21 Induced by the ASK1-p38 Pathway Promotes Mechanical Cell Competition by Attracting Cells (2021)
  • Author(s): Ogawa Motoyuki、Kawarazaki Yosuke、Fujita Yasuyuki、Naguro Isao、Ichijo Hidenori
  • Journal Title: Current Biology Volume: 31 Issue: 5 Pages: 1048-1057
  • DOI: 10.1016/j.cub.2020.11.052
  • Peer Reviewed / Open Access
• [Journal Article] A common SNP risk variant MT1-MMP causative for Dupuytren's disease has a specific defect in collagenolytic activity (2021)
  • Author(s): Itoh Yoshifumi、Ng Michael、Wiberg Akira、Inoue Katsuaki、Hirata Narumi、Paiva Katiucia Batista Silva、Ito Noriko、Dzobo Kim、Sato Nanami、Gifford Valentina、Fujita Yasuyuki、Inada Masaki、Furniss Dominic
  • Journal Title: Matrix Biology Volume: 97 Pages: 20-39
  • DOI: 10.1016/j.matbio.2021.02.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-cell-autonomous migration of RasV12-transformed cells towards the basal side of surrounding normal cells (2021)
  • Author(s): Jebri Imen、Tsujita Kazuya、Fujita Yasuyuki、Itoh Toshiki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 543 Pages: 15-22
  • DOI: 10.1016/j.bbrc.2021.01.031
  • NAID: 120006996928
  • Peer Reviewed
• [Journal Article] PTEN is required for the migration and invasion of Ras‐transformed MDCK cells (2021)
  • Author(s): Yan Lu、Tsujita Kazuya、Fujita Yasuyuki、Itoh Toshiki
  • Journal Title: FEBS Letters Volume: - Issue: 9 Pages: 1303-1312
  • DOI: 10.1002/1873-3468.14053
  • Peer Reviewed
• [Journal Article] ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition (2020)
  • Author(s): Maruyama Takeshi、Sasaki Ayana、Iijima Sayuri、Ayukawa Shiyu、Goda Nobuhito、Tazuru Keisuke、Hashimoto Norikazu、Hayashi Takashi、Kozawa Kei、Sato Nanami、Ishikawa Susumu、Morita Tomoko、Fujita Yasuyuki
  • Journal Title: iScience Volume: 23 Issue: 7 Pages: 101327-101327
  • DOI: 10.1016/j.isci.2020.101327
  • NAID: 120006979756
  • Peer Reviewed / Open Access
• [Journal Article] RasV12 Expression in Microglia Initiates Retinal Inflammation and Induces Photoreceptor Degeneration (2020)
  • Author(s): Moriuchi Yuta、Iwagawa Toshiro、Tsuhako Asano、Koso Hideto、Fujita Yasuyuki、Watanabe Sumiko
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 61 Issue: 13 Pages: 34-34
  • DOI: 10.1167/iovs.61.13.34
  • Peer Reviewed
• [Presentation] 細胞競合の普遍的制御分子の同定とその動作機序の解明 (2022)
  • Author(s): 藤田恭之
  • Organizer: 学術変革領域(A) [競合的コミュニケーションから迫る 多細胞生命システムの自律性] 第1回 領域班会議
• [Presentation] 正常上皮細胞と変異細胞間に生じる細胞競合 (2021)
  • Author(s): 藤田恭之
  • Organizer: 2021年度生理研研究会
  • Invited
• [Presentation] がんの発生から進展における細胞競合 (2021)
  • Author(s): 藤田恭之
  • Organizer: 第80回日本癌学会学術総会
  • Invited
• [Presentation] 哺乳類上皮の癌化における細胞競合 (2020)
  • Author(s): 藤田恭之
  • Organizer: 第41回日本炎症・再生医学会
  • Invited
• [Presentation] 正常細胞と変異細胞間に生じる細胞競合 (2020)
  • Author(s): 藤田恭之
  • Organizer: 第45回日本医用マススペクトル学会年会
  • Invited
• [Presentation] 細胞競合で考える放射線発がん (2020)
  • Author(s): 藤田恭之
  • Organizer: 日本放射線影響学会 第63回大会
  • Invited
• [Presentation] 細胞競合による生体制御とがん(Cell competition in development and cancer) (2020)
  • Author(s): 藤田恭之
  • Organizer: 第43回分子生物学会年会哺乳類上皮の癌化における細胞競合
  • Invited