LAUSR

Description A temporal systems biology screen of premetastatic endothelial cells identified LRG1 as a therapeutic target for restricting metastases. A LaRGe effect on metastases A more complete understanding of the vascular niche as it evolves after surgical resection of cancer is needed. Here, Singhal and colleagues used endothelial cell (EC) transcriptomics and serum proteomics over time to study postsurgical mouse models of spontaneous metastasis, identifying leucine-rich alpha-2 glycoprotein 1 (LRG1) as a molecule produced by ECs in response to tumor-induced systemic inflammation. Increased systemic LRG1 led to greater numbers of perivascular cells in the lungs and increased metastases. LRG1-neutralizing antibody treatment at the time of surgical resection in two spontaneously metastasizing mouse models resulted in decreased metastatic burden and prolonged survival. These findings identify LRG1 as a potential target to restrict metastatic growth. 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.