Department of Biology, Duke University, Durham, NC 27708, USA.
Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Curr Biol. 2019 Mar 4;29(5):823-833.e5. doi: 10.1016/j.cub.2019.01.056. Epub 2019 Feb 21.
Niche cell enwrapment of stem cells and their differentiating progeny is common and provides a specialized signaling and protective environment. Elucidating the mechanisms underlying enwrapment behavior has important basic and clinical significance in not only understanding how niches are formed and maintained but also how they can be engineered and how they are misregulated in human pathologies, such as cancer. Previous work in C. elegans found that, when germ cells, which are enwrapped by somatic gonadal niche cells, are freed into the body cavity, they embed into other tissues. We investigated this phenomenon using live-cell imaging and discovered that ectopic germ cells preferentially induce body-wall muscle to extend cellular processes that enwrap the germ cells, the extent of which was strikingly similar to the distal tip cell (DTC)-germ stem cell niche. Enwrapment was specific for escaped germ cells, and genetic analysis revealed it did not depend on pathways that control cell death and engulfment or muscle arm extension. Instead, using a large-scale RNAi screen and GFP knockin strains, we discovered that the enwrapping behavior of muscle relied upon the same suite of cell-cell adhesion molecules that functioned in the endogenous niche: the C. elegans E-cadherin HMR-1, its intracellular associates α-catenin (HMP-1) and β-catenin (HMP-2), and the L1CAM protein SAX-7. This ectopic niche-like behavior resembles the seed-and-soil model of cancer metastasis and offers a new model to understand factors regulating ectopic niche formation.
龛细胞包裹干细胞及其分化后代的现象很常见，为其提供了一个专门的信号和保护环境。阐明龛细胞包裹行为的机制不仅对于理解龛细胞如何形成和维持具有重要的基础和临床意义，而且对于理解如何对其进行工程化改造以及在人类疾病（如癌症）中如何失调也具有重要意义。之前在秀丽隐杆线虫中的研究发现，当被体细胞生殖嵴龛细胞包裹的生殖细胞被释放到体腔中时，它们会嵌入到其他组织中。我们使用活细胞成像技术研究了这一现象，发现异位生殖细胞优先诱导体壁肌肉延伸细胞过程来包裹生殖细胞，其程度与远端生殖干细胞龛（DTC）中的情况非常相似。包裹是针对逃脱的生殖细胞的，遗传分析表明，它不依赖于控制细胞死亡和吞噬或肌肉臂延伸的途径。相反，我们通过大规模 RNAi 筛选和 GFP 敲入品系发现，肌肉的包裹行为依赖于在天然龛中发挥作用的相同一套细胞-细胞黏附分子：线虫 E-钙黏蛋白 HMR-1、其细胞内伴侣α-连环蛋白（HMP-1）和β-连环蛋白（HMP-2）以及 L1CAM 蛋白 SAX-7。这种异位龛样行为类似于癌症转移的“种子和土壤”模型，为理解调节异位龛形成的因素提供了一个新的模型。
