2. Academic Validation
  3. Differential Ire1 determines loser cell fate in tumor-suppressive cell competition

Differential Ire1 determines loser cell fate in tumor-suppressive cell competition

  • Cell Rep. 2023 Nov 3;42(11):113303. doi: 10.1016/j.celrep.2023.113303.
Jiadong Zheng 1,  Yifan Guo 1,  Changyi Shi 2,  Shuai Yang 3,  Wenyan Xu 4,  Xianjue Ma 5
Affiliations

Affiliations

  • 1 Fudan University, Shanghai 200433, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China.
  • 2 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China.
  • 3 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China.
  • 4 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. Electronic address: xuwenyan@westlake.edu.cn.
  • 5 Fudan University, Shanghai 200433, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. Electronic address: maxianjue@westlake.edu.cn.
PMID: 37924514 DOI: 10.1016/j.celrep.2023.113303
Abstract

Tumor-suppressive cell competition (TSCC) is a conserved surveillance mechanism in which neighboring cells actively eliminate oncogenic cells. Despite overwhelming studies showing that the unfolded protein response (UPR) is dysregulated in various tumors, it remains debatable whether the UPR restrains or promotes tumorigenesis. Here, using Drosophila eye epithelium as a model, we uncover a surprising decisive role of the IRE1 branch of the UPR in regulating cell polarity gene scribble (scrib) loss-induced TSCC. Both mutation and hyperactivation of IRE1 accelerate elimination of scrib clones via inducing Apoptosis and Autophagy, respectively. Unexpectedly, relative IRE1 activity is also crucial for determining loser cell fate, as dysregulating IRE1 signaling in the surrounding healthy cells reversed the "loser" status of scrib clones by decreasing their Apoptosis. Furthermore, we show that IRE1 is required for cell competition in mammalian cells. Together, these findings provide molecular insights into scrib-mediated TSCC and highlight IRE1 as a key determinant of loser cell fate.

Keywords

CP: Cell biology; Drosophila; E-cad; Ire1; UPR; apoptosis; autophagy; cell competition; scribble; tumor.

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