Abstract
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. Follain et al. demonstrate that blood flow forces tune both the arrest and extravasation of circulating tumor cells in vivo. Permissive flow forces allow stable intravascular arrest of circulating tumor cells. Flow forces drive endothelial remodeling around arrested tumor cells, favoring extravasation preceding metastatic outgrowth.
| Original language | English |
|---|---|
| Journal | Developmental Cell |
| Volume | 45 |
| Issue number | 1 |
| Pages (from-to) | 33-52.e12 |
| ISSN | 1534-5807 |
| DOIs | |
| Publication status | Published - 09.04.2018 |
Funding
We thank all members of the Goetz Lab for helpful discussions. We are grateful to Tsukasa Shibue (MIT) and Bob Weinberg (MIT) for providing D2A1 cells and to Richard White (MSKCC) for providing the ZMEL1 cell line. We are very much grateful to Francesca Peri (EMBL) and Kerstin Richter (EMBL) for providing zebrafish embryos. We thank Anita Michel (INSERM U949) and Fabienne Proamer (INSERM U949) from EFS imaging facility for electronic microscopy. We thank Yohan Gerber for help with the Nifedipin and Norepinephrine experiments. We thank Mourad Ismail for the fruitful discussions on flow simulation and Marie Houillon for participating in the simulation setup. We thank Martin Schrob (EMBL) for assistance with electron tomography. We thank Gertraud Orend, Vincent Hyenne (Goetz Lab), and Michaël Poirier for critical reading of the manuscript. We thank Raphaël Gaudin for providing access to the Imaris software. This work has been funded by Plan Cancer (OptoMetaTrap, to J.G. and S.H.) and CNRS IMAG’IN (to S.H., J.G., and C.P.), by the French National Cancer Institute (INCa, MetaCLEM, to J.G and S.H.), and by institutional funds from INSERM and University of Strasbourg . C.P. and V.C. were supported by the Center of Modeling and Simulation of Strasbourg (CEMOSIS), ANR MONU-Vivabrain , and the Labex IRMIA . G.F. is supported by La Ligue Contre le Cancer. N.O. is supported by Plan Cancer. L.M. is supported by an INSERM/Région Alsace PhD fellowship. A.S.A. and G.A. are supported by FRM (Fondation pour la Recherche Médicale). M.A.K. is supported by an EMBL Interdisciplinary Post-doctoral fellowship (EIPOD) under Marie Curie Actions ( COFUND ).
