Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia.
Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia.
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DOI：
10.1016/j.devcel.2016.11.015
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发表时间：
2016-12-19
影响因子：
11.8
通讯作者：
Igaki T
中科院分区：
文献类型：
--
作者：
Vaughen J;Igaki T
细胞在动物发育过程中动态相互作用，以协调生长并预防疾病。例如，细胞间竞争可以清除异常细胞以维持体内平衡。在果蝇中，细胞极性基因 scribble (scrib) 突变体的致瘤细胞在被野生型细胞包围时会主动从上皮细胞中消除。虽然 Scrib 细胞的消除主要取决于 JNK 信号传导，但 JNK 依赖性细胞死亡不能充分解释 Scrib 细胞的消除。因此，JNK 如何执行细胞消除仍然难以捉摸。在这里，我们发现排斥性 Slit-Robo2-Ena 信号在 JNK 下游施加挤压力，通过破坏 E-钙粘蛋白来消除上皮细胞中的划线细胞。虽然 Scrib 细胞中 Slit-Robo2-Ena 的缺失会增强上皮内 Scrib 肿瘤的形成，但 Robo2-Ena 过度激活令人惊讶地会在过度挤压后触发腔内 Scrib 肿瘤的生长。这种突出的信号通过 Slit-Robo2-Ena 和 JNK 之间的正反馈回路被放大。我们的观察结果为多种人类癌症中 Slit-Robo 失调提供了潜在的因果机制。肿瘤抑制程序从发育组织中去除异常细胞。 Vaughen 和 Igaki 认为 Slit-Robo2-Ena 是果蝇上皮细胞消除极性缺陷细胞背后的推动力。虽然 Slit-Robo2-Ena 的缺失允许上皮内形成肿瘤，但 Slit-Robo2-Ena 信号过度激活会引发过度挤压和管腔肿瘤过度生长。
Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers. Tumor-suppressive programs remove aberrant cells from developing tissues. Vaughen and Igaki identify Slit-Robo2-Ena as the extrusive force behind polarity-deficient cell elimination from Drosophila epithelia. While loss of Slit-Robo2-Ena permits tumor formation within the epithelium, Slit-Robo2-Ena signaling hyperactivation triggers excess extrusion and luminal tumor overgrowth.
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通讯作者：
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