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.^1-3 Recent studies have revealed that mechanical forces induce competitive cell-cell interactions in Drosophila.^4-6 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^KD cells).⁷scrib^KD cells are hypersensitive to crowding due to the lower homeostatic density than wild-type (WT) cells,^7,8 and in the context of cell competition, scrib^KD cells are compacted and eliminated by WT cells.^7-10 Although p38 and p53 are involved in this process,^7,10 the molecular mechanism by which WT cells recognize and mechanically eliminate scrib^KD cells remains unclear. Here, we report that scrib^KD cells secrete fibroblast growth factor 21 (FGF21) to drive cell competition. Knockdown of FGF21 in scrib^KD cells or loss of FGFR1 in WT cells suppresses cell competition, suggesting that WT cells recognize scrib^KD cells through FGF21. FGF21-containing culture medium of scrib^KD cells activates cell motility. Moreover, FGF21 promotes the compression and elimination of scrib^KD cells by attracting surrounding WT cells. We also demonstrate that activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway in scrib^KD cells induces FGF21 to drive cell competition. Our findings reveal a mechanism whereby WT cells mechanically eliminate scrib^KD cells and propose a new function for FGF21 in cell-cell communication.