Singhal, M;
Gengenbacher, N;
Pari, AAA;
Kamiyama, M;
Hai, L;
Kuhn, BJ;
Kallenberg, DM;
... Augustin, HG; + view all
(2021)
Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis.
Science Translational Medicine
, 13
(609)
, Article eabe6805. 10.1126/scitranslmed.abe6805.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/scitranslmed.abe6805 |
| Publisher version: | https://doi.org/10.1126/scitranslmed.abe6805 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, ANTI-ANGIOGENIC THERAPY, VESSEL CO-OPTION, ENDOTHELIAL-CELLS, MEDIATES RESISTANCE, TUMOR-GROWTH, EXPRESSION, STAT3, GLIOBLASTOMA, PROGRESSION, ACTIVATION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10139886 |
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