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  3. A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration

A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration

  • Dev Cell. 2022 Oct 10;57(19):2290-2304.e7. doi: 10.1016/j.devcel.2022.09.003.
Naoya Hino 1,  Kimiya Matsuda 2,  Yuya Jikko 3,  Gembu Maryu 4,  Katsuya Sakai 5,  Ryu Imamura 5,  Shinya Tsukiji 6,  Kazuhiro Aoki 7,  Kenta Terai 3,  Tsuyoshi Hirashima 8,  Xavier Trepat 9,  Michiyuki Matsuda 10
Affiliations

Affiliations

  • 1 Research Center for Dynamic Living Systems, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Institute of Science and Technology Austria, 3400 Klosterneuburg, Austria. Electronic address: naoya.hino@ist.ac.at.
  • 2 Research Center for Dynamic Living Systems, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • 3 Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • 4 Division of Quantitative Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan.
  • 5 Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan; WPI-Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
  • 6 Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan; Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan.
  • 7 Division of Quantitative Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan; Quantitative Biology Research Group, Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan; Department of Basic Biology, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan.
  • 8 Research Center for Dynamic Living Systems, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Hakubi Center, Kyoto University, Kyoto, Japan; Japan Science and Technology Agency, Presto, Kawaguchi, Japan.
  • 9 Institute for Bioengineering of Catalonia, Barcelona 08028, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain.
  • 10 Research Center for Dynamic Living Systems, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: matsuda.michiyuki.2c@kyoto-u.ac.jp.
PMID: 36174555 DOI: 10.1016/j.devcel.2022.09.003
Abstract

Upon the initiation of collective cell migration, the cells at the free edge are specified as leader cells; however, the mechanism underlying the leader cell specification remains elusive. Here, we show that lamellipodial extension after the release from mechanical confinement causes sustained extracellular signal-regulated kinase (ERK) activation and underlies the leader cell specification. Live-imaging of Madin-Darby canine kidney (MDCK) cells and mouse epidermis through the use of Förster resonance energy transfer (FRET)-based biosensors showed that leader cells exhibit sustained ERK activation in a hepatocyte growth factor (HGF)-dependent manner. Meanwhile, follower cells exhibit oscillatory ERK activation waves in an epidermal growth factor (EGF) signaling-dependent manner. Lamellipodial extension at the free edge increases the cellular sensitivity to HGF. The HGF-dependent ERK activation, in turn, promotes lamellipodial extension, thereby forming a positive feedback loop between cell extension and ERK activation and specifying the cells at the free edge as the leader cells. Our findings show that the integration of physical and biochemical cues underlies the leader cell specification during collective cell migration.

Keywords

ERK; FRET; HGF; collective cell migration; feedback regulation; lamellipodia; leader cell specification; signal transduction; traction force; wound healing.

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