FGF21 Induced by the ASK1-p38 Pathway Promotes Mechanical Cell Competition by Attracting Cells.

Cell competition is a social cellular phenomenon in which unfit cells are selectively eliminated to maintain tissue homeostasis. Recent studies have revealed that mechanical forces induce competitive cell-cell interactions in Drosophila. This mechanical cell competition has also been reported to play an important role in mammalian cells, using Madin-Darby canine kidney (MDCK) cells depleted of a polarity regulator Scribble in a tetracycline-inducible manner (scrib cells).scrib cells are hypersensitive to crowding due to the lower homeostatic density than wild-type (WT) cells, and in the context of cell competition, scrib cells are compacted and eliminated by WT cells. Although p38 and p53 are involved in this process, the molecular mechanism by which WT cells recognize and mechanically eliminate scrib cells remains unclear. Here, we report that scrib cells secrete fibroblast growth factor 21 (FGF21) to drive cell competition. Knockdown of FGF21 in scrib cells or loss of FGFR1 in WT cells suppresses cell competition, suggesting that WT cells recognize scrib cells through FGF21. FGF21-containing culture medium of scrib cells activates cell motility. Moreover, FGF21 promotes the compression and elimination of scrib cells by attracting surrounding WT cells. We also demonstrate that activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway in scrib cells induces FGF21 to drive cell competition. Our findings reveal a mechanism whereby WT cells mechanically eliminate scrib cells and propose a new function for FGF21 in cell-cell communication.