Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

• Published in: Scientific reports Vol. 11; no. 1; p. 13144
• Main Authors: Follain, Gautier, Osmani, Naël, Gensbittel, Valentin, Asokan, Nandini, Larnicol, Annabel, Mercier, Luc, Garcia-Leon, Maria Jesus, Busnelli, Ignacio, Pichot, Angelique, Paul, Nicodème, Carapito, Raphaël, Bahram, Seiamak, Lefebvre, Olivier, Goetz, Jacky G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-06-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/555; 631/154/556; 631/67; 631/67/1347; 631/80; 631/80/2373; 692/699/67/2321; Animals; Animals, Genetically Modified; Biochemistry, Molecular Biology; Biomechanics; Blood flow; Blood Flow Velocity - drug effects; Cancer; Embryo, Nonmammalian - blood supply; Embryo, Nonmammalian - physiology; Embryos; Endothelial cells; Endothelium, Vascular - physiology; Extravasation; Gene Expression Regulation, Neoplastic; Gene Ontology; Genomics; Hemorheology; Human Umbilical Vein Endothelial Cells; Humanities and Social Sciences; Humans; In Vitro Techniques; Intravital Microscopy; Life Sciences; Mechanics; Metastases; Metastasis; Microfluidics; Microscopy, Confocal; Molecular modelling; multidisciplinary; Neoplastic Cells, Circulating; Physics; Protein-tyrosine kinase; Quinazolines - pharmacology; Quinazolines - therapeutic use; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Science; Science (multidisciplinary); Signal Transduction - physiology; Sunitinib - pharmacology; Sunitinib - therapeutic use; Transendothelial and Transepithelial Migration - drug effects; Tumor cells; Tumors; Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-1 - physiology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - physiology; Vascular endothelial growth factor receptors; Zebrafish - embryology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-92515-2

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.