Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT 06519, USA
Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT 06519, USA.
Dis Model Mech. 2019 Oct 7;12(10):dmm039727. doi: 10.1242/dmm.039727.
Targeted cell migration plays important roles in developmental biology and disease processes, including in metastasis. tumors exhibit traits characteristic of human cancers, providing a powerful model to study developmental and cancer biology. We now find that cells derived from eye-disc tumors also display organ-specific metastasis, invading receptive organs but not wing disc. Toll receptors are known to affect innate immunity and the tumor inflammatory microenvironment by modulating the NF-κB pathway. Our RNA interference (RNAi) screen and genetic analyses show that Toll-6 is required for migration and invasion of the tumor cells. Further, receptive organs express Toll ligands [Spätzle (Spz) family molecules], and ectopic Spz expression renders the wing disc receptive to metastasis. Finally, Toll-6 promotes metastasis by activating JNK signaling, a key regulator of cell migration. Hence, we report Toll-6 and Spz as a new pair of guidance molecules mediating organ-specific metastatic behavior and highlight a novel signaling mechanism for Toll-family receptors.
靶向细胞迁移在发育生物学和疾病过程中发挥着重要作用，包括转移。肿瘤表现出具有人类癌症特征的特征，为研究发育和癌症生物学提供了强大的模型。我们现在发现，来源于眼盘肿瘤的细胞也表现出器官特异性转移，侵袭接受器官而不是翅膀盘。 Toll 受体通过调节 NF-κB 途径影响先天免疫和肿瘤炎症微环境。我们的 RNA 干扰 (RNAi) 筛选和遗传分析表明， Toll-6 是肿瘤细胞迁移和侵袭所必需的。此外，接受器官表达 Toll 配体（Spätzle (Spz) 家族分子），并且异位 Spz 表达使翅膀盘对转移具有接受性。最后， Toll-6 通过激活 JNK 信号通路促进转移，JNK 信号通路是细胞迁移的关键调节剂。因此，我们报告 Toll-6 和 Spz 作为一对新的指导分子，介导器官特异性转移行为，并强调 Toll 家族受体的一种新的信号机制。
