Previous studies have revealed that, at the initial step of carcinogenesis, transformed cells are often eliminated from epithelia via cell competition with the surrounding normal cells. In this study, we performed cell competition-based high-throughput screening for chemical compounds using cultured epithelial cells and confocal microscopy. PLX4720 was identified as a hit compound that promoted apical extrusion of RasV12-transformed cells surrounded by normal epithelial cells. Knockdown/knockout of ZAK, a target of PLX4720, substantially enhanced the apical elimination of RasV12 cells in vitro and in vivo. ZAK negatively modulated the accumulation or activation of multiple cell competition regulators. Moreover, PLX4720 treatment promoted apical elimination of RasV12-transformed cells in vivo and suppressed the formation of potentially precancerous tumors. This is the first report demonstrating that a cell competition-promoting chemical drug facilitates apical elimination of transformed cells in vivo, providing a new dimension in cancer preventive medicine.

先前的研究表明，在致癌的初始阶段，转化的细胞通常通过与周围正常细胞的细胞竞争而从上皮细胞中清除。在这项研究中，我们使用培养的上皮细胞和共聚焦显微镜对化合物进行了基于细胞竞争的高通量筛选。PLX4720被鉴定为一种命中化合物，可促进被正常上皮细胞包围的RasV12转化细胞的顶端挤出。ZAK的击倒/敲除，PLX4720的目标，在体外和体内显着增强了RasV12细胞的根尖消除。ZAK负调节多个细胞竞争调节剂的积累或激活。此外，PLX4720治疗促进根尖消除RasV12转化的细胞体内抑制了潜在的癌前肿瘤的形成。这是第一份证明促进细胞竞争的化学药物在体内促进根尖消除转化细胞的研究，为癌症预防医学提供了新的领域。