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

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 Ohashi, Jun Koseki, Hirotaka Takahashi, Hideshi Yokoyama, Yukihiro Shiraki, Atsushi Enomoto, Sohei Abe, Yoku Hayakawa, Tetsuo Ushiku, Michihiro Mutoh, Yasuyuki Fujita and Shunsuke Kon ()
Additional contact information
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

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42774-6

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