Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community.A classical model is the removal of polarity-deficient clones,such as the p...Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community.A classical model is the removal of polarity-deficient clones,such as the precancerous scribble(scrib)mutant clones,in Drosophila imaginal discs.The activation of Ras,Yki,or Notch signaling robustly reverses the scrib mutant clonal fate from elimination to tumorous growth.Whether these signals converge to adopt a common mechanism to overcome the elimination pressure posed by cell competition remains unclear.Using single-cell transcriptomics,we find that a critical converging point downstream of Ras,Yki,and Notch signals is the upregulation of Upd2,an IL-6 family cytokine.Overexpression of Upd2 is sufficient to rescue the scrib mutant clones from elimination.Depletion of Upd2 blocks the growth of the scrib mutant clones with active Ras,Yki,and Notch signals.Moreover,Upd2 overexpression promotes robust intestinal stem cell(ISC)proliferation,while Upd2 is intrinsically required in ISCs for the growth of the adult intestine.Together,these results identify Upd2 as a crucial cell fitness factor that sustains tissue growth but can potentiate tumorigenesis when deregulated.展开更多
基金supported by grants to Yan Yan from the Research Grants Council of the Hong Kong Special Administrative Region(GRF16103620,GRF16104324,T13-602/21N)from Shenzhen Science and Technology Innovation Commission(JCYJ20200109140201722)+1 种基金to Toyotaka Ishibashi from the National Natural Science Foundation of China(32170548)to Zongzhao Zhai from the National Natural Science Foundation of China(32170509 and 31871469).
文摘Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community.A classical model is the removal of polarity-deficient clones,such as the precancerous scribble(scrib)mutant clones,in Drosophila imaginal discs.The activation of Ras,Yki,or Notch signaling robustly reverses the scrib mutant clonal fate from elimination to tumorous growth.Whether these signals converge to adopt a common mechanism to overcome the elimination pressure posed by cell competition remains unclear.Using single-cell transcriptomics,we find that a critical converging point downstream of Ras,Yki,and Notch signals is the upregulation of Upd2,an IL-6 family cytokine.Overexpression of Upd2 is sufficient to rescue the scrib mutant clones from elimination.Depletion of Upd2 blocks the growth of the scrib mutant clones with active Ras,Yki,and Notch signals.Moreover,Upd2 overexpression promotes robust intestinal stem cell(ISC)proliferation,while Upd2 is intrinsically required in ISCs for the growth of the adult intestine.Together,these results identify Upd2 as a crucial cell fitness factor that sustains tissue growth but can potentiate tumorigenesis when deregulated.
