2. Academic Validation
  3. Wnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway

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

  • Nat Commun. 2023 Nov 3;14(1):7048. doi: 10.1038/s41467-023-42774-6.
Kazuki Nakai 1,  Hancheng Lin 1,  Shotaro Yamano 2,  Shinya Tanaka 3,  Sho Kitamoto 4,  Hitoshi Saitoh 5,  Kenta Sakuma 1,  Junpei Kurauchi 1,  Eilma Akter 1,  Masamitsu Konno 1,  Kojiro Ishibashi 6,  Ryo Kamata 5,  Akihiro Ohashi 5,  Jun Koseki 7,  Hirotaka Takahashi 8,  Hideshi Yokoyama 9,  Yukihiro Shiraki 10,  Atsushi Enomoto 10,  Sohei Abe 11,  Yoku Hayakawa 11,  Tetsuo Ushiku 12,  Michihiro Mutoh 13,  Yasuyuki Fujita 3,  Shunsuke Kon 14
Affiliations

Affiliations

  • 1 Division of Cancer Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, 278-0022, Japan.
  • 2 Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Kanagawa, 257-0015, Japan.
  • 3 Department of Molecular Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
  • 4 Division of Microbiology and Immunology, The WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, 565-0871, Japan.
  • 5 Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, 277-8577, Japan.
  • 6 Division of Tumor Cell Biology and Bioimaging, Cancer Research Institute, Kanazawa University, Kakuma-Machi, Kanazawa, 920-1192, Japan.
  • 7 Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
  • 8 Division of Cell-Free Sciences, Proteo-Science Center, Ehime University, Matsuyama, 790-8577, Japan.
  • 9 Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan.
  • 10 Department of Pathology, Nagoya University Hospital, Nagoya, 466-8550, Japan.
  • 11 Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
  • 12 Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
  • 13 Department of Molecular-Targeting Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
  • 14 Division of Cancer Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, 278-0022, Japan. [email protected].
PMID: 37923722 DOI: 10.1038/s41467-023-42774-6
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.

Figures
Products