转移
癌症研究
生物
原发性肿瘤
基质细胞蛋白
癌症
免疫学
医学
细胞生物学
细胞外基质
遗传学
作者
Mahak Singhal,Nicolas Gengenbacher,Ashik Ahmed Abdul Pari,Miki Kamiyama,Ling Hai,Bianca J. Kuhn,David Kallenberg,Shubhada R. Kulkarni,Carlotta Camilli,Stephanie F. Preuß,Barbara Leuchs,Carolin Mogler,Elisa Espinet,Eva Besemfelder,Danijela Heide,Mathias Heikenwälder,Martin R. Sprick,Andreas Trumpp,Jeroen Krijgsveld,Matthias Schlesner
标识
DOI:10.1126/scitranslmed.abe6805
摘要
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.
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