Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis.
Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis.
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时间多组学鉴定LRG1作为转移的血管小生境指导者。
DOI：
10.1126/scitranslmed.abe6805
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发表时间：
2021-09
影响因子：
17.1
通讯作者：
Augustin HG
中科院分区：
文献类型：
--
作者：
Singhal M;Gengenbacher N;Abdul Pari AA;Kamiyama M;Hai L;Kuhn BJ;Kallenberg DM;Kulkarni SR;Camilli C;Preuß SF;Leuchs B;Mogler C;Espinet E;Besemfelder E;Heide D;Heikenwalder M;Sprick MR;Trumpp A;Krijgsveld J;Schlesner M;Hu J;Moss SE;Greenwood J;Augustin HG
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是决定性的，并且可能是转移的限速因素。这种串扰的分子本质超出了迄今为止知之甚少的候选基因方法。采用内皮细胞（EC）散装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。时间多组学研究显示，原发性肿瘤系统性地重新编程身体的血管内皮细胞，以扰乱体内平衡，并为转移性生长预处理血管生态位。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。肺EC基因表达和分泌组的比较分析确定转化生长因子-β（TGFβ）途径特异性因子LRG 1（富含亮氨酸的α-2-糖蛋白1）是转移的早期指导者。在存在原发性肿瘤的情况下，EC以信号转导和转录激活因子3（STAT 3）依赖性方式全身性上调LRG 1。回顾性临床研究的荟萃分析揭示了癌症患者血清中LRG 1浓度的相应上调。在功能上，LRG 1的全身上调通过增加促转移NG 2+血管周围细胞的数量来促进小鼠的转移。反过来，Lrg 1的基因缺失阻碍了肺转移瘤的生长。术后辅助给予LRG 1中和抗体可延迟转移性肿瘤的生长并增加总生存期。因此，该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LRG 1确定为转移的治疗靶点。
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 crosstalk is beyond candidate gene approaches hitherto poorly understood. Employing 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 upregulated LRG1 in a Signal transducer and activator of transcription 3 (STAT3)-dependent manner. A meta-analysis of retrospective clinical studies revealed a corresponding upregulation of LRG1 concentrations in the serum of cancer patients. Functionally, systemic upregulation of LRG1 promoted metastasis in mice by increasing the number of pro-metastatic 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. The study has thereby established the systems map of early primary tumor-induced vascular changes and identified LRG1 as a therapeutic target for metastasis.
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DOI：
10.1084/jem.20030077
发表时间：
2003-11-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kano A;Wolfgang MJ;Gao Q;Jacoby J;Chai GX;Hansen W;Iwamoto Y;Pober JS;Flavell RA;Fu XY
通讯作者：
Fu XY
影响因子：
17.1
作者：
Allen E;Jabouille A;Rivera LB;Lodewijckx I;Missiaen R;Steri V;Feyen K;Tawney J;Hanahan D;Michael IP;Bergers G
通讯作者：
Bergers G
影响因子：
3.7
作者：
Kramer G;Woolerton Y;van Straalen JP;Vissers JP;Dekker N;Langridge JI;Beynon RJ;Speijer D;Sturk A;Aerts JM
通讯作者：
Aerts JM
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
2.9
作者：
Furukawa, Kenta;Kawamoto, Koichi;Nagano, Hiroaki
通讯作者：
Nagano, Hiroaki