Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Division of Life Science, Center for Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Curr Biol. 2018 Jun 4;28(11):1756-1767.e6. doi: 10.1016/j.cub.2018.04.022. Epub 2018 May 24.
Normal epithelial tissue exerts an intrinsic tumor-suppressive effect against oncogenically transformed cells. In Drosophila imaginal epithelium, clones of oncogenic polarity-deficient cells mutant for scribble (scrib) or discs large (dlg) are eliminated by cell competition when surrounded by wild-type cells. Here, through a genetic screen in Drosophila, we identify Serpin5 (Spn5), a secreted negative regulator of Toll signaling, as a crucial factor for epithelial cells to eliminate scrib mutant clones from epithelium. Downregulation of Spn5 in wild-type cells leads to elevation of Toll signaling in neighboring scrib cells. Strikingly, forced activation of Toll signaling or Toll-related receptor (TRR) signaling in scrib clones transforms scrib cells from losers to supercompetitors, resulting in tumorous overgrowth of mutant clones. Mechanistically, Toll activation in scrib clones leads to c-Jun N-terminal kinase (JNK) activation and F-actin accumulation, which cause strong activation of the Hippo pathway effector Yorkie that blocks cell death and promotes cell proliferation. Our data suggest that Spn5 secreted from normal epithelial cells acts as a component of the extracellular surveillance system that facilitates elimination of pre-malignant cells from epithelium.
正常的上皮组织对致癌转化细胞具有内在的肿瘤抑制作用。在果蝇的 imaginal 上皮中，当 scribble（scrib）或 discs large（dlg）突变的致癌极性缺陷细胞的克隆被周围的野生型细胞包围时，它们会通过细胞竞争被消除。在这里，我们通过果蝇的遗传筛选，鉴定出 Serpin5（Spn5），一种 Toll 信号的分泌负调节剂，是上皮细胞从上皮中消除 scrib 突变克隆的关键因素。在野生型细胞中下调 Spn5 会导致相邻 scrib 细胞中 Toll 信号的升高。引人注目的是，在 scrib 克隆中强制激活 Toll 信号或 Toll 相关受体（TRR）信号会使 scrib 细胞从失败者转变为超级竞争者，导致突变克隆的肿瘤性过度生长。在机制上，scrib 克隆中 Toll 的激活导致 c-Jun N 端激酶（JNK）的激活和 F-肌动蛋白的积累，从而导致 Hippo 通路效应物 Yorkie 的强烈激活，阻止细胞死亡并促进细胞增殖。我们的数据表明，正常上皮细胞分泌的 Spn5 作为细胞外监测系统的一个组成部分，促进了上皮前恶性细胞的消除。
