Sequential oncogenic mutations influence cell competition
Sequential oncogenic mutations influence cell competition
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DOI：
10.1016/j.cub.2021.06.064
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发表时间：
2021-09-27
期刊：
影响因子：
9.2
通讯作者：
Fujita, Yasuyuki
中科院分区：
文献类型：
--
作者：
Kohashi, Koki;Mori, Yusuke;Fujita, Yasuyuki
在癌发生的初始阶段，新出现的转化细胞通常通过与周围正常细胞的细胞竞争而从上皮层中消除。例如，当被正常细胞包围时，癌蛋白RasV12转化的细胞被挤出到上皮细胞的顶腔中。在癌症发展过程中，多种致癌突变在上皮组织内积累。然而，细胞竞争是否以及如何参与这一过程仍然是难以捉摸的。在这项研究中，使用哺乳动物细胞培养模型系统，我们已经调查了Ras和肿瘤抑制蛋白Scribble的连续突变后会发生什么。当Ras突变发生在Scribble敲低背景下时，Scribble/Ras双突变细胞的顶端挤出强烈减弱。此外，在与Scribble/Ras细胞的边界处，Scribble敲低的细胞经常经历凋亡，并被邻近的Scribble/Ras细胞积极吞噬。在果蝇上皮组织中也观察到Scribble/Ras双突变体和Scribble单突变体细胞之间的可比较的凋亡和吞噬表型。此外，在Scribble/Ras细胞中，线粒体膜电位增强，导致线粒体活性氧（ROS）增加。抑制线粒体膜电位或ROS产生减少了周围Scribble敲低细胞的凋亡和吞噬，表明线粒体代谢在双突变细胞和单突变细胞之间的竞争性相互作用中起着关键作用。此外，mTOR（雷帕霉素激酶的机制靶点）在这些过程的下游起作用。这些结果意味着连续的致癌突变可以深刻地影响细胞竞争，从失败者到赢家的转变。进一步的研究将为基于细胞竞争的癌症治疗开辟新的途径，从而阻止肿瘤内更恶性群体的克隆扩增。
At the initial stage of carcinogenesis, newly emerging transformed cells are often eliminated from epithelial layers via cell competition with the surrounding normal cells. For instance, when surrounded by normal cells, oncoprotein RasV12-transformed cells are extruded into the apical lumen of epithelia. During cancer development, multiple oncogenic mutations accumulate within epithelial tissues. However, it remains elusive whether and how cell competition is also involved in this process. In this study, using a mammalian cell culture model system, we have investigated what happens upon the consecutive mutations of Ras and tumor suppressor protein Scribble. When Ras mutation occurs under the Scribble-knockdown background, apical extrusion of Scribble/Ras double-mutant cells is strongly diminished. In addition, at the boundary with Scribble/Ras cells, Scribble-knockdown cells frequently undergo apoptosis and are actively engulfed by the neighboring Scribble/Ras cells. The comparable apoptosis and engulfment phenotypes are also observed in Drosophila epithelial tissues between Scribble/Ras double-mutant and Scribble single-mutant cells. Furthermore, mitochondrial membrane potential is enhanced in Scribble/Ras cells, causing the increased mitochondrial reactive oxygen species (ROS). Suppression of mitochondrial membrane potential or ROS production diminishes apoptosis and engulfment of the surrounding Scribble-knockdown cells, indicating that mitochondrial metabolism plays a key role in the competitive interaction between double-and single-mutant cells. Moreover, mTOR (mechanistic target of rapamycin kinase) acts downstream of these processes. These results imply that sequential oncogenic mutations can profoundly influence cell competition, a transition from loser to winner. Further studies would open new avenues for cell competition-based cancer treatment, thereby blocking clonal expansion of more malignant populations within tumors.