Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis

Singhal, Mahak; Gengenbacher, Nicolas; Pari, Ashik Ahmed Abdul; Kamiyama, Manabu; Lü, Hai; Kuhn, Bianca J.; Kallenberg, David; Kulkarni, Shubhada Rajabhau; Camilli, Carlotta; Preuß, Stephanie F.; Leuchs, Barbara; Mogler, Carolin; Espinet, Elisa; Besemfelder, Eva; Heide, Danijela; Heikenwälder, Mathias; Sprick, Martin R.; Trumpp, Andreas; Krijgsveld, Jeroen; Schlesner, Matthias; Hu, Junhao; Moss, Stephen E.; Greenwood, John; Augustin, Hellmut G.

doi:10.1126/scitranslmed.abe6805

Cited by 46 publications

(46 citation statements)

References 69 publications

(114 reference statements)

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“…In addition, LRG1 has been identified as a useful biomarker to distinguish between patients with active or inactive systemic juvenile idiopathic arthritis and in patients with rheumatoid arthritis during Tocilizumab treatment 8 , 59 . Taking these reports into account, together with other studies where the IL-6/STAT3 axis has been implicated in the regulation of LRG1 20 , 60 – 62 and a study showing that IL-6 promotes defective angiogenesis 34 , we explored the potential transcriptional regulation of LRG1 by IL-6. We showed that IL-6 activated LRG1 transcription to promote angiogenesis with reduced mural cell coverage through the phosphorylation and binding of STAT3 to its conserved consensus site on the LRG1 gene promoter.…”

Section: Discussionmentioning

confidence: 98%

“…This is currently most evident in the eye and kidney, where it plays a central role in the vascular dysfunction observed in models of retinal neovascularisation and diabetic kidney disease and is consistent with raised LRG1 levels in patients with these diseases 15 – 17 . Moreover, in cancer, where there is an emerging body of evidence for a pathogenic role for LRG1 14 , 18 , the induction of LRG1 in tumour endothelial cells has also been shown to contribute to pathological neovascularisation 19 and priming the vascular metastatic niche 20 establishing this secreted glycoprotein as a new vasculopathic molecule.…”

Section: Introductionmentioning

confidence: 99%

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Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

Dritsoula

Dowsett

Pilotti

et al. 2022

Sci Rep

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Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In Lrg1−/− explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated LRG1 transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the LRG1 promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced LRG1 expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

Dritsoula

Dowsett

Pilotti

et al. 2022

Sci Rep

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“…In conditions of altered homeostasis that typically accompany disease, transcription of the Lrg1 gene has been reported to be highly upregulated in endothelial cells [ 4 , 70 , 73 – 75 ], several types of epithelial cells [ 15 , 17 , 26 , 28 , 68 , 76 ], fibroblasts [ 34 , 57 , 70 , 77 ] and myeloid cells [ 11 , 56 , 72 , 78 – 81 ] including microglia [ 82 ] (Fig. 5 ).…”

Section: Reviewmentioning

confidence: 99%

“…3 F). As a result, it plays a key role in conditioning the vascular bed for metastatic colonization, possibly by increasing the number of pro-metastatic perivascular cells [ 75 ]. This study also revealed that the contribution of LRG1 secreted by the vascular compartment is far more important than that synthesised by the liver, and that targeting LRG1 therapeutically may have utility in restricting metastatic cancer.…”

Section: Reviewmentioning

confidence: 99%

LRG1: an emerging player in disease pathogenesis

et al. 2022

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The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1−/− mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.

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“…Some of these changes may affect blood vessels, as recently shown for leucine-rich alpha-2-glycoprotein 1 (ref. 54 ). However, our findings indicate that the four vascular niche genes are not induced by secreted factors from primary tumors.…”

Section: Discussionmentioning

confidence: 99%

Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs

et al. 2022

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Disseminated cancer cells frequently lodge near vasculature in secondary organs. However, our understanding of the cellular crosstalk invoked at perivascular sites is still rudimentary. Here, we identify intercellular machinery governing formation of a pro-metastatic vascular niche during breast cancer colonization in the lung. We show that specific secreted factors, induced in metastasis-associated endothelial cells (ECs), promote metastasis in mice by enhancing stem cell properties and the viability of cancer cells. Perivascular macrophages, activated via tenascin C (TNC) stimulation of Toll-like receptor 4 (TLR4), were shown to be crucial in niche activation by secreting nitric oxide (NO) and tumor necrosis factor (TNF) to induce EC-mediated production of niche components. Notably, this mechanism was independent of vascular endothelial growth factor (VEGF), a key regulator of EC behavior and angiogenesis. However, targeting both macrophage-mediated vascular niche activation and VEGF-regulated angiogenesis resulted in added potency to curb lung metastasis in mice. Together, our findings provide mechanistic insights into the formation of vascular niches in metastasis.

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Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis

Abstract: A systems-biology endothelial cell screen has established the vascular systems map of early metastatic colonization and identified the TGFb pathway specifier as therapeutic target of metastasis.

Cited by 46 publications

References 69 publications

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

LRG1: an emerging player in disease pathogenesis

Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs

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