Institute of Molecular and Cell Biology, Proteos, Singapore 138673.
Proc Natl Acad Sci U S A. 2012 Feb 7;109(6):2027-32. doi: 10.1073/pnas.1115260109. Epub 2012 Jan 23.
Directed cell migration is important for normal animal development and physiology. The process can also be subverted by tumor cells to invade other tissues and to metastasize. Some cells, such as leukocytes, migrate individually; other cells migrate together in groups or sheets, called collective cell migration. Guidance of individually migrating cells depends critically on subcellularly localized perception and transduction of signals. For collective cell migration, guidance could result from cells within a group achieving different signaling levels, with directionality then encoded in the collective rather than in individual cells. Here we subject this collective guidance hypothesis to direct tests, using migration of border cells during Drosophila oogenesis as our model system. These cells normally use two receptor tyrosine kinases (RTKs), PDGF/VEGF-related receptor (PVR) and EGFR, to read guidance cues secreted by the oocyte. Elevated but delocalized RTK signaling in one cell of the cluster was achieved by overexpression of PVR in the absence of ligand or by overexpression of fusion receptors unable to detect Drosophila ligands; alternatively, Rac was photoactivated centrally within a single cell. In each case, one cell within the group was in a high signal state, whereas others were in low signal states. The high signal cell directed cluster movement effectively. We conclude that differences in cell signaling states are sufficient to direct collective migration and are likely a substantial contributor to normal guidance. Cell signaling states could manifest as differences in gene expression or metabolite levels and thus differ substantially from factors normally considered when analyzing eukaryotic cell guidance.
定向细胞迁移对正常动物发育和生理功能非常重要。肿瘤细胞也可以利用这个过程转移到其他组织并发生转移。有些细胞，如白细胞，是单独迁移的；而其他细胞则以群体或薄片的形式一起迁移，称为集体细胞迁移。单个迁移细胞的定向取决于亚细胞定位感知和信号转导。对于集体细胞迁移，定向可能来自于群体内的细胞达到不同的信号水平，然后在集体中而不是在单个细胞中编码方向。在这里，我们直接测试了这个集体导向假说，以果蝇卵子发生过程中的边缘细胞迁移作为我们的模型系统。这些细胞通常使用两种受体酪氨酸激酶（RTK），PDGF/VEGF 相关受体（PVR）和 EGFR，来读取卵母细胞分泌的导向信号。通过在没有配体的情况下过表达 PVR 或过表达无法检测到果蝇配体的融合受体，在一个细胞簇中的一个细胞中实现了升高但弥散的 RTK 信号；或者在单个细胞的中心用光激活 Rac。在每种情况下，细胞簇中的一个细胞处于高信号状态，而其他细胞处于低信号状态。高信号细胞有效地指导了细胞簇的运动。我们得出结论，细胞信号状态的差异足以指导集体迁移，并且可能是正常导向的重要贡献者。细胞信号状态可能表现为基因表达或代谢物水平的差异，因此与分析真核细胞导向时通常考虑的因素有很大不同。
