Hemodynamic forces tune the arrest, adhesion and extravasation of circulating tumor cells

Gautier Follain (1) , Nael Osmani (1) , Sofia Azevedo (1) , Guillaume Allio (1) , Luc Mercier (1) , Matthia Karreman (2) , Gergely Solecki (3) , Maria Jesus Garcia-Leon (1) , Olivier Lefebvre (1) , Nina Fekonja (1) , Claudia Hille (4) , Vincent Chabannes (5) , Guillaume Dollé (5) , Thibaut Métivet (5) , François Der Hovsepian (5) , Christophe Prud'Homme (5) , Angélique Pichot (1) , Nicodème Paul (1) , Raphaël Carapito (1) , Siamak Bahram (1) , Bernhard Ruthensteiner (6) , André Kemmling (7) , Susanne Siemonsen (4) , Tanja Schneider (4) , Jens Fiehler (4) , Markus Glatzel (4) , Frank Winkler (3) , Yannick Schwab (2) , Klaus Pantel (4) , Sebastien Harlepp (1, 8) , Jacky G Goetz (1)

1 IRM - Immuno-Rhumatologie Moléculaire
2 EMBL - European Molecular Biology Laboratory [Heidelberg]
3 Heidelberg University Hospital [Heidelberg]
4 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
5 IRMA - Institut de Recherche Mathématique Avancée
6 SNSB - Zoologische Staatssammlung Muenchen
7 UKSH - University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein
8 IPCMS - Institut de Physique et Chimie des Matériaux de Strasbourg

Metastatic seeding is driven by cell-intrinsic and environmental cues, yet the contribution of biomechanics is poorly known. We aim to elucidate the impact of blood flow on the arrest and the extravasation of circulating tumor cells (CTCs) in vivo. Using the zebrafish embryo, we show that arrest of CTCs occurs in vessels with favorable flow profiles where flow forces control the adhesion efficacy of CTCs to the endothelium. We biophysically identified the threshold values of flow and adhesion forces allowing successful arrest of CTCs. In addition, flow forces fine-tune tumor cell extravasation by impairing the remodeling properties of the endothelium. Importantly, we also observe endothelial remodeling at arrest sites of CTCs in mouse brain capillaries. Finally, we observed that human supratentorial brain metastases preferably develop in areas with low perfusion. These results demonstrate that hemodynamic profiles at metastatic sites regulate key steps of extravasation preceding metastatic outgrowth.

Domaines: Cancer; Modélisation et simulation

Gautier Follain, Nael Osmani, Sofia Azevedo, Guillaume Allio, Luc Mercier, et al.. Hemodynamic forces tune the arrest, adhesion and extravasation of circulating tumor cells. Developmental Cell, 2018, 45 (1), pp.33-52.e12. ⟨10.1016/j.devcel.2018.02.015⟩. ⟨hal-01694694⟩