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Wnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway

Author

Listed:
  • Kazuki Nakai

    (Tokyo University of Science, Noda)

  • Hancheng Lin

    (Tokyo University of Science, Noda)

  • Shotaro Yamano

    (Japan Organization of Occupational Health and Safety)

  • Shinya Tanaka

    (Kyoto University)

  • Sho Kitamoto

    (Osaka University)

  • Hitoshi Saitoh

    (National Cancer Center)

  • Kenta Sakuma

    (Tokyo University of Science, Noda)

  • Junpei Kurauchi

    (Tokyo University of Science, Noda)

  • Eilma Akter

    (Tokyo University of Science, Noda)

  • Masamitsu Konno

    (Tokyo University of Science, Noda)

  • Kojiro Ishibashi

    (Kanazawa University, Kakuma-Machi)

  • Ryo Kamata

    (National Cancer Center)

  • Akihiro Ohashi

    (National Cancer Center)

  • Jun Koseki

    (Nagoya University Graduate School of Medicine)

  • Hirotaka Takahashi

    (Ehime University)

  • Hideshi Yokoyama

    (Tokyo University of Science, Noda)

  • Yukihiro Shiraki

    (Nagoya University Hospital)

  • Atsushi Enomoto

    (Nagoya University Hospital)

  • Sohei Abe

    (University of Tokyo)

  • Yoku Hayakawa

    (University of Tokyo)

  • Tetsuo Ushiku

    (University of Tokyo)

  • Michihiro Mutoh

    (Kyoto Prefectural University of Medicine)

  • Yasuyuki Fujita

    (Kyoto University)

  • Shunsuke Kon

    (Tokyo University of Science, Noda)

Abstract

Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the internal or external factors that compromise cell competition and provoke carcinogenesis remain elusive. In this study, we examine the effect of sequential accumulation of gene mutations, mimicking multi-sequential carcinogenesis on RasV12-induced cell competition in intestinal epithelial tissues. Consequently, we find that the directionality of RasV12-cell extrusion in Wnt-activated epithelia is reversed, and transformed cells are delaminated into the basal lamina via non-cell autonomous MMP21 upregulation. Subsequently, diffusively infiltrating, transformed cells develop into highly invasive carcinomas. The elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. We further demonstrate that the NF-κB-MMP21 axis is significantly bolstered in early colorectal carcinoma in humans. Collectively, this study shows that cells with high mutational burdens exploit cell competition for their benefit by behaving as unfit cells, endowing them with an invasion advantage.

Suggested Citation

  • Kazuki Nakai & Hancheng Lin & Shotaro Yamano & Shinya Tanaka & Sho Kitamoto & Hitoshi Saitoh & Kenta Sakuma & Junpei Kurauchi & Eilma Akter & Masamitsu Konno & Kojiro Ishibashi & Ryo Kamata & Akihiro , 2023. "Wnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42774-6
    DOI: 10.1038/s41467-023-42774-6
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