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

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 can...

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Main Authors: Hongu, Tsunaki (Author) , Pein, Maren (Author) , Insua-Rodríguez, Jacob (Author) , Gutjahr, Ewgenija (Author) , Mattavelli, Greta (Author) , Meier, Jasmin (Author) , Decker, Kristin (Author) , Descot, Arnaud (Author) , Bozza, Matthias (Author) , Harbottle, Richard P. (Author) , Trumpp, Andreas (Author) , Sinn, Peter (Author) , Riedel, Angela (Author) , Oskarsson, Thordur (Author)
Format: Article (Journal)
Language:English
Published: 25 April 2022
In: Nature cancer
Year: 2022, Volume: 3, Issue: 4, Pages: 486-504
ISSN:2662-1347
DOI:10.1038/s43018-022-00353-6
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s43018-022-00353-6
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s43018-022-00353-6
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Author Notes:Tsunaki Hongu, Maren Pein, Jacob Insua-Rodríguez, Ewgenija Gutjahr, Greta Mattavelli, Jasmin Meier, Kristin Decker, Arnaud Descot, Matthias Bozza, Richard Harbottle, Andreas Trumpp, Hans-Peter Sinn, Angela Riedel and Thordur Oskarsson
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Summary: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.
Item Description:Gesehen am 30.05.2022
Physical Description:Online Resource
ISSN:2662-1347
DOI:10.1038/s43018-022-00353-6

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