Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells

Gautier Follain; Naël Osmani; Ana Sofia Azevedo; Guillaume Allio; Luc Mercier; Matthia A. Karreman; Gergely Solecki; Marìa Jesùs Garcia Leòn; Olivier Lefebvre; Nina Fekonja; Claudia Hille; Vincent Chabannes; Guillaume Dollé; Thibaut Metivet; François Der Hovsepian; Christophe Prudhomme; Angélique Pichot; Nicodème Paul; Raphaël Carapito; Siamak Bahram; Bernhard Ruthensteiner; André Kemmling; Susanne Siemonsen; Tanja Schneider; Jens Fiehler; Markus Glatzel; Frank Winkler; Yannick Schwab; Klaus Pantel; Sébastien Harlepp; Jacky G. Goetz

doi:10.1016/j.devcel.2018.02.015

Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells

Gautier Follain, Naël Osmani, Ana Sofia Azevedo, Guillaume Allio, Luc Mercier, Matthia A. Karreman, Gergely Solecki, Marìa Jesùs Garcia Leòn, Olivier Lefebvre, Nina Fekonja, Claudia Hille, Vincent Chabannes, Guillaume Dollé, Thibaut Metivet, François Der Hovsepian, Christophe Prudhomme, Angélique Pichot, Nicodème Paul, Raphaël Carapito, Siamak BahramBernhard Ruthensteiner, André Kemmling, Susanne Siemonsen, Tanja Schneider, Jens Fiehler, Markus Glatzel, Frank Winkler, Yannick Schwab, Klaus Pantel, Sébastien Harlepp, Jacky G. Goetz^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Neuroradiologie

272 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Developmental Cell
Jahrgang	45
Ausgabenummer	1
Seiten (von - bis)	33-52.e12
ISSN	1534-5807
DOIs	https://doi.org/10.1016/j.devcel.2018.02.015
Publikationsstatus	Veröffentlicht - 09.04.2018

Fördermittel

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 ).

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10.1016/j.devcel.2018.02.015

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Follain, G., Osmani, N., Azevedo, A. S., Allio, G., Mercier, L., Karreman, M. A., Solecki, G., Garcia Leòn, M. J., Lefebvre, O., Fekonja, N., Hille, C., Chabannes, V., Dollé, G., Metivet, T., Hovsepian, F. D., Prudhomme, C., Pichot, A., Paul, N., Carapito, R., ... Goetz, J. G. (2018). Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells. Developmental Cell, 45(1), 33-52.e12. https://doi.org/10.1016/j.devcel.2018.02.015

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title = "Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells",

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.",

author = "Gautier Follain and Na{\"e}l Osmani and Azevedo, \{Ana Sofia\} and Guillaume Allio and Luc Mercier and Karreman, \{Matthia A.\} and Gergely Solecki and \{Garcia Le{\`o}n\}, \{Mar{\`i}a Jes{\`u}s\} and Olivier Lefebvre and Nina Fekonja and Claudia Hille and Vincent Chabannes and Guillaume Doll{\'e} and Thibaut Metivet and Hovsepian, \{Fran{\c c}ois Der\} and Christophe Prudhomme and Ang{\'e}lique Pichot and Nicod{\`e}me Paul and Rapha{\"e}l Carapito and Siamak Bahram and Bernhard Ruthensteiner and Andr{\'e} Kemmling and Susanne Siemonsen and Tanja Schneider and Jens Fiehler and Markus Glatzel and Frank Winkler and Yannick Schwab and Klaus Pantel and S{\'e}bastien Harlepp and Goetz, \{Jacky G.\}",

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doi = "10.1016/j.devcel.2018.02.015",

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Follain, G, Osmani, N, Azevedo, AS, Allio, G, Mercier, L, Karreman, MA, Solecki, G, Garcia Leòn, MJ, Lefebvre, O, Fekonja, N, Hille, C, Chabannes, V, Dollé, G, Metivet, T, Hovsepian, FD, Prudhomme, C, Pichot, A, Paul, N, Carapito, R, Bahram, S, Ruthensteiner, B, Kemmling, A, Siemonsen, S, Schneider, T, Fiehler, J, Glatzel, M, Winkler, F, Schwab, Y, Pantel, K, Harlepp, S & Goetz, JG 2018, 'Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells', Developmental Cell, Jg. 45, Nr. 1, S. 33-52.e12. https://doi.org/10.1016/j.devcel.2018.02.015

TY - JOUR

T1 - Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells

AU - Follain, Gautier

AU - Osmani, Naël

AU - Azevedo, Ana Sofia

AU - Allio, Guillaume

AU - Mercier, Luc

AU - Karreman, Matthia A.

AU - Solecki, Gergely

AU - Garcia Leòn, Marìa Jesùs

AU - Lefebvre, Olivier

AU - Fekonja, Nina

AU - Hille, Claudia

AU - Chabannes, Vincent

AU - Dollé, Guillaume

AU - Metivet, Thibaut

AU - Hovsepian, François Der

AU - Prudhomme, Christophe

AU - Pichot, Angélique

AU - Paul, Nicodème

AU - Carapito, Raphaël

AU - Bahram, Siamak

AU - Ruthensteiner, Bernhard

AU - Kemmling, André

AU - Siemonsen, Susanne

AU - Schneider, Tanja

AU - Fiehler, Jens

AU - Glatzel, Markus

AU - Winkler, Frank

AU - Schwab, Yannick

AU - Pantel, Klaus

AU - Harlepp, Sébastien

AU - Goetz, Jacky G.

PY - 2018/4/9

Y1 - 2018/4/9

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85044898270

U2 - 10.1016/j.devcel.2018.02.015

DO - 10.1016/j.devcel.2018.02.015

M3 - Journal articles

C2 - 29634935

AN - SCOPUS:85044898270

SN - 1534-5807

VL - 45

SP - 33-52.e12

JO - Developmental Cell

JF - Developmental Cell

IS - 1

ER -

Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells

Abstract

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