Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer1. Here we use mouse models of breast and lung cancer to investigate whether endothelial cells also have active 'instructive' roles in the dissemination of cancer. We purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumours. Deep sequencing revealed that metastatic tumours induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoural (low Slit2 expression) compartments. Endothelial-derived SLIT2 protein and its receptor ROBO1 promoted the migration of cancer cells towards endothelial cells and intravasation. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoural Slit2 enhanced metastatic progression. We identified double-stranded RNA derived from tumour cells as an upstream signal that induces expression of endothelial SLIT2 by acting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium that drives intravasation and metastasis. These findings reveal that endothelial cells have a direct instructive role in driving metastatic dissemination, and demonstrate that a single gene (Slit2) can promote or suppress cancer progression depending on its cellular source.

中文翻译：

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内皮中 TLR3-SLIT2 轴的肿瘤激活驱动转移

血管通过提供营养和氧气来支持肿瘤，同时还充当癌症传播的管道1。在这里，我们使用乳腺癌和肺癌的小鼠模型来研究内皮细胞是否在癌症传播中也具有积极的“指导”作用。我们从高转移和低转移肿瘤中纯化了基因标记的内皮核糖体及其相关转录物。深度测序显示，转移性肿瘤在内皮细胞中诱导轴突引导基因 Slit2 的表达，在内皮细胞（高 Slit2 表达）和肿瘤（低 Slit2 表达）区室之间建立了差异表达。内皮衍生的 SLIT2 蛋白及其受体 ROBO1 促进癌细胞向内皮细胞和血管内的迁移。删除内皮细胞 Slit2 抑制了乳腺癌和肺癌小鼠模型中的转移性传播。相反，肿瘤 Slit2 的缺失增强了转移进展。我们将源自肿瘤细胞的双链 RNA 鉴定为上游信号，通过作用于 RNA 感应受体 TLR3 诱导内皮 SLIT2 的表达。因此，一组内源性逆转录病毒元件 RNA 在转移细胞中上调并在细胞外检测到。因此，癌细胞选择先天性 RNA 感应来诱导内皮细胞趋化信号通路，从而驱动血管内渗入和转移。这些发现表明，内皮细胞在驱动转移性传播中具有直接指导作用，并证明单个基因 (Slit2) 可以根据其细胞来源促进或抑制癌症进展。