Tumoural activation of TLR3-SLIT2 axis in endothelium drives metastasis.
Tumoural activation of TLR3-SLIT2 axis in endothelium drives metastasis.
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内皮细胞中TLR3-SLIT2轴的肿瘤激活驱动转移。
DOI：
10.1038/s41586-020-2774-y
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发表时间：
2020-10
期刊：
影响因子：
64.8
通讯作者：
Tavazoie SF
中科院分区：
文献类型：
--
作者：
Tavora B;Mederer T;Wessel KJ;Ruffing S;Sadjadi M;Missmahl M;Ostendorf BN;Liu X;Kim JY;Olsen O;Welm AL;Goodarzi H;Tavazoie SF
血管通过提供营养和氧气来支持肿瘤，同时也是癌症传播的管道。在这里，我们使用小鼠模型的乳腺癌和肺癌，以调查是否内皮细胞也有积极的“指导”作用，在癌症的传播。我们从高转移性和低转移性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，转移性肿瘤诱导了轴突导向基因Slit 2在内皮中的表达，建立了内皮（高Slit 2表达）和肿瘤（低Slit 2表达）区室之间的差异表达。内皮源性SLIT 2蛋白及其受体ROBO 1促进癌细胞向内皮细胞的迁移和内渗。在乳腺癌和肺癌的小鼠模型中，删除内皮细胞Slit2抑制了转移性播散。相反，肿瘤Slit2的缺失增强了转移进展。我们鉴定了来自肿瘤细胞的双链RNA作为上游信号，其通过作用于RNA敏感受体TLR3诱导内皮SLIT 2的表达。因此，一组内源性逆转录病毒元件RNA在转移性细胞中上调并在细胞外检测。因此，癌细胞吸收先天性RNA传感以诱导内皮中的趋化性信号传导途径，其驱动内渗和转移。这些发现揭示了内皮细胞在驱动转移性传播中具有直接的指导作用，并证明了单个基因（Slit2）可以根据其细胞来源促进或抑制癌症进展。
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 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.
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影响因子：
64.5
作者：
Brose, K;Bland, KS;Kidd, T
通讯作者：
Kidd, T
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
7.3
作者：
Kawasaki T;Kawai T
通讯作者：
Kawai T
影响因子：
8
作者：
Dallol, A;Krex, D;Latif, F
通讯作者：
Latif, F
影响因子：
5.3
作者：
GUY, CT;CARDIFF, RD;MULLER, WJ
通讯作者：
MULLER, WJ