Tumoural activation of TLR3–SLIT2 axis in endothelium drives metastasis
Tavora B, Mederer T, Wessel KJ, et al. Tumoural activation of TLR3-SLIT2 axis in endothelium drives metastasis. Nature 2020.
Correspondence to：stavazoie@rockefeller.edu
Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer. 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 purifed 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 identifed 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 fndings 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.
血管通過提供營養和氧氣來維持腫瘤生長，並且是著腫瘤傳播的通道。在此，我們使用小鼠乳腺癌和肺癌模型來研究上皮細胞是否在腫瘤的播散中也具有激活「指令」作用。我們從高轉移性和低轉移性腫瘤中純化了帶有基因標記的內皮核糖體及其相關轉錄本。深度測序提示轉移性腫瘤誘導軸突導向基因Slit2在內皮細胞中的表達，建立內皮細胞(高Slit2表達)和腫瘤(低Slit2表達)間的差異表達.內皮細胞驅動SLIT2蛋白以及它的受體ROBO1促進了癌症細胞向內皮細胞的轉移和內滲。敲除內皮細胞Slit2基因抑制了乳腺癌和肺癌小鼠模型的轉移播散。相反，腫瘤Slit2的缺失增強了轉移進展。我們發現來自腫瘤細胞的雙鏈RNA是一種上遊信號，通過作用於RNA感應受體TLR3誘導內皮SLIT2的表達。據此，一系列內源性逆轉錄病毒RNA在轉移性細胞中上調,在細胞外可被檢測到。因此癌症細胞通過固有的RNA感應來誘導內皮細胞中的趨化信號通路，驅動內滲和轉移。這些發現揭示了內皮細胞在驅動轉移播散中擁有一個直接的指令作用，並證實了Slit2基因可以根據其細胞來源以促進或者一直癌症的進展。
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