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
大鼠肉瘤(rat sarcoma,Ras)基因是实体肿瘤中最常见的原癌基因,由于突变亚型中缺乏药理学上可靶向的口袋,Ras历来被认为是不可成药的靶点。然而,药物设计的改进最终导致了对活性或非活性状态的突变鼠类肉瘤病毒癌基因(kirsten rat sarco...大鼠肉瘤(rat sarcoma,Ras)基因是实体肿瘤中最常见的原癌基因,由于突变亚型中缺乏药理学上可靶向的口袋,Ras历来被认为是不可成药的靶点。然而,药物设计的改进最终导致了对活性或非活性状态的突变鼠类肉瘤病毒癌基因(kirsten rat sarcoma viral oncogene,Kras)具有选择性的抑制剂的开发。其中一些抑制剂已被证明对Kras G12C/G12D突变癌症患者有效,并已成为实践的改变。癌细胞和肿瘤微环境中RAS信号传导的理解不断提高,逐渐探究出新的药物或联合治疗的潜力,目前正在临床试验中进行探索。本文阐述了Ras突变的作用机制及黑色素瘤中Ras突变的特点及近年来该领域的研究进展,旨在展示该突变患者的治疗现状,并对各种新型治疗方法的数据进行归纳和总结,为临床实践方案提供新的治疗思路。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.
