Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

Abstract Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tu...

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Autores principales:	Gautier Follain, Naël Osmani, Valentin Gensbittel, Nandini Asokan, Annabel Larnicol, Luc Mercier, Maria Jesus Garcia-Leon, Ignacio Busnelli, Angelique Pichot, Nicodème Paul, Raphaël Carapito, Seiamak Bahram, Olivier Lefebvre, Jacky G. Goetz
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6130e5f27801400da5a956453d118a77
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spelling	oai:doaj.org-article:6130e5f27801400da5a956453d118a772021-12-02T16:05:54ZImpairing flow-mediated endothelial remodeling reduces extravasation of tumor cells10.1038/s41598-021-92515-22045-2322https://doaj.org/article/6130e5f27801400da5a956453d118a772021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92515-2https://doaj.org/toc/2045-2322Abstract Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.Gautier FollainNaël OsmaniValentin GensbittelNandini AsokanAnnabel LarnicolLuc MercierMaria Jesus Garcia-LeonIgnacio BusnelliAngelique PichotNicodème PaulRaphaël CarapitoSeiamak BahramOlivier LefebvreJacky G. GoetzNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gautier Follain Naël Osmani Valentin Gensbittel Nandini Asokan Annabel Larnicol Luc Mercier Maria Jesus Garcia-Leon Ignacio Busnelli Angelique Pichot Nicodème Paul Raphaël Carapito Seiamak Bahram Olivier Lefebvre Jacky G. Goetz Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells
description	Abstract Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.
format	article
author	Gautier Follain Naël Osmani Valentin Gensbittel Nandini Asokan Annabel Larnicol Luc Mercier Maria Jesus Garcia-Leon Ignacio Busnelli Angelique Pichot Nicodème Paul Raphaël Carapito Seiamak Bahram Olivier Lefebvre Jacky G. Goetz
author_facet	Gautier Follain Naël Osmani Valentin Gensbittel Nandini Asokan Annabel Larnicol Luc Mercier Maria Jesus Garcia-Leon Ignacio Busnelli Angelique Pichot Nicodème Paul Raphaël Carapito Seiamak Bahram Olivier Lefebvre Jacky G. Goetz
author_sort	Gautier Follain
title	Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells
title_short	Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells
title_full	Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells
title_fullStr	Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells
title_full_unstemmed	Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells
title_sort	impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6130e5f27801400da5a956453d118a77
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Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

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