Mutant p53-Expressing Cells Undergo Necroptosis via Cell Competition with the Neighboring Normal Epithelial Cells

Publication date: 26 June 2018
Source:Cell Reports, Volume 23, Issue 13
Author(s): Hirotaka Watanabe, Kojiro Ishibashi, Hiroki Mano, Sho Kitamoto, Nanami Sato, Kazuya Hoshiba, Mugihiko Kato, Fumihiko Matsuzawa, Yasuto Takeuchi, Takanobu Shirai, Susumu Ishikawa, Yuka Morioka, Toshiaki Imagawa, Kazuyasu Sakaguchi, Suguru Yonezawa, Shunsuke Kon, Yasuyuki Fujita
p53 is a tumor suppressor protein, and its missense mutations are frequently found in human cancers. During the multi-step progression of cancer, p53 mutations generally accumulate at the mid or late stage, but not in the early stage, and the underlying mechanism is still unclear. In this study, using mammalian cell culture and mouse ex vivo systems, we demonstrate that when p53R273H- or p53R175H-expressing cells are surrounded by normal epithelial cells, mutant p53 cells undergo necroptosis and are basally extruded from the epithelial monolayer. When mutant p53 cells alone are present, cell death does not occur, indicating that necroptosis results from cell competition with the surrounding normal cells. Furthermore, when p53R273H mutation occurs within RasV12-transformed epithelia, cell death is strongly suppressed and most of the p53R273H-expressing cells remain intact. These results suggest that the order of oncogenic mutations in cancer development could be dictated by cell competition.

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Teaser

Watanabe et al. demonstrate that mutant p53 cells undergo necroptosis and are eliminated from epithelia via cell competition with surrounding normal cells. Moreover, the eradication of mutant p53 cells is suppressed within RasV12-transformed epithelia, suggesting that the order of oncogenic mutations in cancer development could be dictated by cell competition.


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