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 prometastatic 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 revealed that blood flow modulated several signaling pathways in endothelial cells. More specifically, we observed that VEGFR signaling was significantly enhanced. 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 with sunitinib, a pan-inhibitor of VEGFR signaling. Embryos treated with sunitinib displayed reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of 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.Highlights-Flow profiles that are permissive for metastasis stimulate the VEGFR pathway-Flow-dependent VEGFR signaling favors extravasation of CTCs through endothelial remodeling-Inhibition of VEGFR signaling suppresses early flow-driven endothelial response

The cancer cell secretome drives cooperative manipulation of the tumour microenvironment to accelerate tumourigenesis

“…This cancer cell-derived exosomal paracrine pathway resulted in the upregulation of angiogenic pathways, with myofibroblasts acting as the intermediate player 49 . Strikingly, Follain and colleagues have highlighted that extravasation and endothelial remodelling is partly blood flow dependent and leads to increased metastases 50 , 51 . Their studies revealed that the vascular endothelium wall was actively remodelled around the extravasating circulating tumour cell (CTC), and hemodynamic cues from the sheer force of blood flow activated VEGFR pathways to encourage the exit of the cancer cell towards a metastatic site 51 .…”

“…Strikingly, Follain and colleagues have highlighted that extravasation and endothelial remodelling is partly blood flow dependent and leads to increased metastases 50 , 51 . Their studies revealed that the vascular endothelium wall was actively remodelled around the extravasating circulating tumour cell (CTC), and hemodynamic cues from the sheer force of blood flow activated VEGFR pathways to encourage the exit of the cancer cell towards a metastatic site 51 . Thus, although this review focusses on the cancer secretome, the work by Follain et al .…”