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

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 pro-motes 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 auto-phagy, respectively. Unexpectedly, relative Ire1 activity is also crucial for determining loser cell fate, as dys-regulating Ire1 signaling in the surrounding healthy cells reversed the loserstatus 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.

Automated summary

This study reveals the important role of Ire1 in cell competition, regulating the fate of loser cells through controlling apoptosis and autophagy, and provides molecular insights into scrib-mediated TSCC.