TY - JOUR
T1 - Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells
AU - Follain, Gautier
AU - Osmani, Naël
AU - Gensbittel, Valentin
AU - Asokan, Nandini
AU - Larnicol, Annabel
AU - Mercier, Luc
AU - Garcia-Leon, Maria Jesus
AU - Busnelli, Ignacio
AU - Pichot, Angelique
AU - Paul, Nicodème
AU - Carapito, Raphaël
AU - Bahram, Seiamak
AU - Lefebvre, Olivier
AU - Goetz, Jacky G.
N1 - Funding Information:
This work has been funded by Plan Cancer (OptoMetaTrap to JG) and CNRS IMAG’IN (to JG) and INCa (to JG, PLBIO-2014-151, PLBIO 2015-140 and PLBIO 2016-164) and by institutional funds from INSERM and University of Strasbourg. NO is supported by Plan Cancer 2014-2019 (OptoMetaTrap) and the Association pour la Recherche contre le Cancer. GF was supported by La Ligue Contre le Cancer and University of Strasbourg. MJGL is funded by University of Strasbourg and LM was supported by Region Alsace and INSERM. Current work is funded by ITMO Cancer of AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé, National Alliance for Life Sciences & Health) within the framework of the Cancer Plan Cancer (Nanotumor, to JG), la Ligue Contre le Cancer (“Equipe Labellisée” to JG) and IdEx Attractivité program (University of Strasbourg to NO).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108808710&partnerID=8YFLogxK
U2 - 10.1038/s41598-021-92515-2
DO - 10.1038/s41598-021-92515-2
M3 - Article
C2 - 34162963
AN - SCOPUS:85108808710
SN - 2045-2322
VL - 11
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 13144
ER -