Metastasis is the primary cause of cancer-related mortality. Tumor cell interactions with cells of the vessel wall are decisive and potentially rate-limiting for metastasis. The molecular nature of this cross-talk is, beyond candidate gene approaches, hitherto poorly understood. Using endothelial cell (EC) bulk and single-cell transcriptomics in combination with serum proteomics, we traced the evolution of the metastatic vascular niche in surgical models of lung metastasis. Temporal multiomics revealed that primary tumors systemically reprogram the body’s vascular endothelium to perturb homeostasis and to precondition the vascular niche for metastatic growth. The vasculature with its enormous surface thereby serves as amplifier of tumor-induced instructive signals. Comparative analysis of lung EC gene expression and secretome identified the transforming growth factor–β (TGFβ) pathway specifier LRG1, leucine-rich alpha-2-glycoprotein 1, as an early instructor of metastasis. In the presence of a primary tumor, ECs systemically up-regulated LRG1 in a signal transducer and activator of transcription 3 (STAT3)–dependent manner. A meta-analysis of retrospective clinical studies revealed a corresponding up-regulation of LRG1 concentrations in the serum of patients with cancer. Functionally, systemic up-regulation of LRG1 promoted metastasis in mice by increasing the number of prometastatic neural/glial antigen 2 (NG2)+ perivascular cells. In turn, genetic deletion of Lrg1 hampered growth of lung metastasis. Postsurgical adjuvant administration of an LRG1-neutralizing antibody delayed metastatic growth and increased overall survival. This study has established a systems map of early primary tumor-induced vascular changes and identified LRG1 as a therapeutic target for metastasis.

中文翻译：

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时间多组学将 LRG1 确定为转移的血管生态位指导者。

转移是癌症相关死亡的主要原因。肿瘤细胞与血管壁细胞的相互作用对于转移是决定性的并且可能是限制速率的。除了候选基因方法之外，迄今为止，人们对这种串扰的分子性质知之甚少。利用内皮细胞（EC）本体和单细胞转录组学与血清蛋白质组学相结合，我们追踪了肺转移手术模型中转移性血管生态位的演变。时间多组学揭示，原发性肿瘤系统性地重新编程身体的血管内皮，以扰乱体内平衡并为转移性生长预先调节血管生态位。因此，具有巨大表面的脉管系统充当肿瘤诱导的指导信号的放大器。对肺 EC 基因表达和分泌组的比较分析确定了转化生长因子-β (TGFβ) 途径特异因子 LRG1（富含亮氨酸的 α-2-糖蛋白 1）作为转移的早期指导者。在存在原发性肿瘤的情况下，ECs 以信号转导器和转录激活剂 3 (STAT3) 依赖性方式系统性上调 LRG1。一项回顾性临床研究的荟萃分析显示，癌症患者血清中 LRG1 浓度相应上调。从功能上讲，LRG1 的全身上调通过增加促转移性神经/胶质抗原 2 (NG2)+ 血管周围细胞的数量来促进小鼠的转移。反过来，Lrg1 的基因缺失阻碍了肺转移的生长。术后辅助施用 LRG1 中和抗体可延迟转移生长并提高总体生存率。这项研究建立了早期原发性肿瘤诱导的血管变化的系统图，并将 LRG1 确定为转移的治疗靶点。