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1. Compressive stress triggers fibroblasts spreading over cancer cells to generate carcinoma in situ organization

Author

Fabien Bertillot, Laetitia Andrique, Carlos Ureña Martin, Olivier Zajac, Ludmilla de Plater, Michael M. Norton, Aurélien Richard, Kevin Alessandri, Basile G. Gurchenkov, Florian Fage, Atef Asnacios, Christophe Lamaze, Moumita Das, Jean- Léon Maître, Pierre Nassoy, and Danijela Matic Vignjevic

Subjects
Biology (General), QH301-705.5
Abstract

Abstract At the early stage of tumor progression, fibroblasts are located at the outer edges of the tumor, forming an encasing layer around it. In this work, we have developed a 3D in vitro model where fibroblasts’ layout resembles the structure seen in carcinoma in situ. We use a microfluidic encapsulation technology to co-culture fibroblasts and cancer cells within hollow, permeable, and elastic alginate shells. We find that in the absence of spatial constraint, fibroblasts and cancer cells do not mix but segregate into distinct aggregates composed of individual cell types. However, upon confinement, fibroblasts enwrap cancer cell spheroid. Using a combination of biophysical methods and live imaging, we find that buildup of compressive stress is required to induce fibroblasts spreading over the aggregates of tumor cells. We propose that compressive stress generated by the tumor growth might be a mechanism that prompts fibroblasts to form a capsule around the tumor.

Published
2024
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2. Optineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division

Author

Serena Petracchini, Daniel Hamaoui, Anne Doye, Atef Asnacios, Florian Fage, Elisa Vitiello, Martial Balland, Sebastien Janel, Frank Lafont, Mukund Gupta, Benoit Ladoux, Jerôme Gilleron, Teresa M. Maia, Francis Impens, Laurent Gagnoux-Palacios, Mads Daugaard, Poul H. Sorensen, Emmanuel Lemichez, and Amel Mettouchi

Subjects
Science
Abstract

Uropathogenic strains of Escherichia coli (UPEC) are a leading cause of urinary tract infections (UTIs) and invasion involves Rho GTPase members, notably Rac1, to drive actin cytoskeleton rearrangement leading to engulfment. Here, Petracchini et al. provide evidence of an ECM stiffnessmodulated role of Optineurin (OPTN), which regulates HACE1-dependant Rac1 activity and thus controls integrinmediated mechanotransduction and bacterial invasion.

Published
2022
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3. Transient cell stiffening triggered by magnetic nanoparticle exposure

Author

Jose E. Perez, Florian Fage, David Pereira, Ali Abou-Hassan, Sophie Asnacios, Atef Asnacios, and Claire Wilhelm

Subjects
Magnetic nanoparticles, Nano-bio interface, Single cell rheology, Parallel plate rheometer, Biotechnology, TP248.13-248.65, Medical technology, R855-855.5
Abstract

Abstract Background The interactions between nanoparticles and the biological environment have long been studied, with toxicological assays being the most common experimental route. In parallel, recent growing evidence has brought into light the important role that cell mechanics play in numerous cell biological processes. However, despite the prevalence of nanotechnology applications in biology, and in particular the increased use of magnetic nanoparticles for cell therapy and imaging, the impact of nanoparticles on the cells’ mechanical properties remains poorly understood. Results Here, we used a parallel plate rheometer to measure the impact of magnetic nanoparticles on the viscoelastic modulus G*(f) of individual cells. We show how the active uptake of nanoparticles translates into cell stiffening in a short time scale (

Published
2021
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4. All-in-one rheometry and nonlinear rheology of multicellular aggregates

Author

Gaëtan Mary, François Mazuel, Vincent Nier, Florian Fage, Irène Nagle, Louisiane Devaud, Jean-Claude Bacri, Sophie Asnacios, Atef Asnacios, Cyprien Gay, Philippe Marcq, Claire Wilhelm, and Myriam Reffay

Subjects
Cell Adhesion, Rheology, Actins
Abstract

Tissues are generally subjected to external stresses, a potential stimulus for their differentiation or remodeling. While single-cell rheology has been extensively studied leading to controversial results about nonlinear response, mechanical tissue behavior under external stress is still poorly understood, in particular, the way individual cell properties translate at the tissue level. Herein, using magnetic cells we were able to form perfectly monitored cellular aggregates (magnetic molding) and to deform them under controlled applied stresses over a wide range of timescales and amplitudes (magnetic rheometer). We explore the rheology of these minimal tissue models using both standard assays (creep and oscillatory response) as well as an innovative broad spectrum solicitation coupled with inference analysis thus being able to determine in a single experiment the best rheological model. We find that multicellular aggregates exhibit a power-law response with nonlinearities leading to tissue stiffening at high stress. Moreover, we reveal the contribution of intracellular (actin network) and intercellular components (cell-cell adhesions) in this aggregate rheology.

Published
2022
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5. Optineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division

Author

Laurent Gagnoux, Serena Petracchini, Benoit Ladoux, Amel Mettouchi, Martial Balland, Mads Daugaard, Mukund Gupta, Emmanuel Lemichez, Francis Impens, Poul H. Sorensen, Sébastien Janel, Elisa Vitiello, Anne Doye, Frank Lafont, Florian Fage, Atef Asnacios, Teresa Mendes Maia, Daniel Hamaoui, Jerome Gilleron, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Equipe labellisée Ligue contre le Cancer, Matière et Systèmes Complexes (MSC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Cellular Microbiology and Physics of Infection Group [Lille] (CMPI), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Universiteit Gent = Ghent University (UGENT), Institut de Biologie Valrose (IBV), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Vancouver Prostate Centre [Vancouver General Hospital] (VPC), Vancouver General Hospital, University of British Columbia (UBC), Toxines bactériennes - Bacterial Toxins, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This study was supported by institutional INSERM and Institut Pasteur fundings, 'Investments for the Future' LabEx SIGNALIFE ANR-11-LABX-0028-01 and grants from the Ligue Nationale contre le Cancer (LNCC labellisation and RS20/75-63), Association pour la Recherche contre le Cancer (ARC PJA20191209650), EPIC-XS, project number 823839, funded by the Horizon 2020 programme of the European Union (PRC-5074) and FRM-Piraud prize to E.L., Bio-SPC 'Contrat Doctoral' PhD fellowship to S.P., LNCC PhD fellowship to D.H., the Vancouver Prostate Centre to M.D., and Team Finn and The Ride to Concur Cancer to P.H.S., Fundings from ANR to A.A. ('ImmunoMeca' ANR-12-BSV5-0007-01, 'Initiatives d’excellence' Idex ANR-11-IDEX-0005-02, and 'Labex Who Am I?' ANR-11-LABX-0071)and to F.L. (ANR-10-EQPX-04-01), and from FEDER (12001407) to F.L. B.L. acknowledges financial supports from the Mechanobiology Institute, the European Research Council under the European Union's 7th Framework Programme (FP7/2007-2013) / ERC n° 617233 and NUS-USPC collaborative program., ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-12-BSV5-0007,ImmunoMeca,Caractérisation du rôle de la mécanique dans l'immunité: vers un modèle intégré de l'activation des cellules T(2012), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-11-LABX-0071,WHO AM I,Determinants de l'Identité : de la molécule à l'individu(2011), ANR-10-EQPX-0004,Imaginex BioMed,Plateau de microscopie de criblage à haut débit et d'analyse à très haute résolution(2010), European Project: 617233,EC:FP7:ERC,ERC-2013-CoG,DURACELL(2014), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Nice Sophia Antipolis (... - 2019) (UNS), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), National University of Singapore (NUS), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University [Belgium] (UGENT), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
rac1 GTP-Binding Protein, Integrins, Cell division, Mechanotransduction, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Integrin, General Physics and Astronomy, RAC1, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mechanotransduction, Cellular, General Biochemistry, Genetics and Molecular Biology, Extracellular matrix, Focal adhesion, Integrin signalling, 03 medical and health sciences, 0302 clinical medicine, Medicine and Health Sciences, Cyclin D1, 030304 developmental biology, Optineurin, 0303 health sciences, CNF1 toxin, Multidisciplinary, biology, Chemistry, Ubiquitination, Biology and Life Sciences, Cell migration, General Chemistry, Hostpathogen interaction, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Cell biology, E3 ubiquitin ligase, biology.protein, Rac1 GTPase, Cell Division, 030217 neurology & neurosurgery, Tumour suppressor
Abstract

Extracellular matrix (ECM) elasticity is perceived by cells via focal adhesion structures, which transduce mechanical cues into chemical signalling to conform cell behavior. Although the contribution of ECM compliance to the control of cell migration or division is extensively studied, little is reported regarding infectious processes. We study this phenomenon with the extraintestinal Escherichia coli pathogen UTI89. We show that UTI89 takes advantage, via its CNF1 toxin, of integrin mechanoactivation to trigger its invasion into cells. We identify the HACE1 E3 ligase-interacting protein Optineurin (OPTN) as a protein regulated by ECM stiffness. Functional analysis establishes a role of OPTN in bacterial invasion and integrin mechanical coupling and for stimulation of HACE1 E3 ligase activity towards the Rac1 GTPase. Consistent with a role of OPTN in cell mechanics, OPTN knockdown cells display defective integrin-mediated traction force buildup, associated with limited cellular invasion by UTI89. Nevertheless, OPTN knockdown cells display strong mechanochemical adhesion signalling, enhanced Rac1 activation and increased cyclin D1 translation, together with enhanced cell proliferation independent of ECM stiffness. Together, our data ascribe a new function to OPTN in mechanobiology. Uropathogenic strains of Escherichia coli (UPEC) are a leading cause of urinary tract infections (UTIs) and invasion involves Rho GTPase members, notably Rac1, to drive actin cytoskeleton rearrangement leading to engulfment. Here, Petracchini et al. provide evidence of an ECM stiffnessmodulated role of Optineurin (OPTN), which regulates HACE1-dependant Rac1 activity and thus controls integrinmediated mechanotransduction and bacterial invasion.

Published
2022
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6. All-in-one rheology of multicellular aggregates

Author

Gaëtan Mary, François Mazuel, Vincent Nier, Florian Fage, Irène Nagle, Louisiane Devaud, Jean-Claude Bacri, Sophie Asnacios, Atef Asnacios, Cyprien Gay, Philippe Marcq, Claire Wilhelm, and Myriam Reffay

Subjects
Multicellular organism, Rheology, Polymer science, Chemistry
Abstract

Tissues are generally subjected to external stresses, a potential stimulus for their differentiation or remodelling. While single-cell rheology has been extensively studied, mechanical tissue behavior under external stress is still poorly known because of a lack of adapted set-ups. Herein we introduce magnetic techniques designed both to form aggregates of controlled size, shape and content (magnetic molding) and to deform them under controlled applied stresses over a wide range of timescales and amplitudes (magnetic rheometer). We explore the rheology of multicellular aggregates (F9 cells) using both standard assays (creep and oscillatory response) and an innovative broad spectrum solicitation coupled with inference analysis. We find that multicellular aggregates exhibit a power-law response with non-linearities leading to tissue stiffening at high stress. Comparing magnetic measurements on aggregates to isolated F9 cells characterization by parallel-plates rheometry, we reveal the role of cell-cell adhesions in tissue mechanics. Thanks to its versatility, the magnetic rheometer thus stands as an essential tool to investigate model tissue rheology.

Published
2021
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7. Transient cell stiffening triggered by magnetic nanoparticle exposure

Author

Sophie Asnacios, Claire Wilhelm, Ali Abou-Hassan, Florian Fage, Atef Asnacios, Jose E. Perez, David Pereira, Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), PHysicochimie des Electrolytes et Nanosystèmes InterfaciauX (PHENIX), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Faculté de Physique (UFR 925), and Sorbonne Université (SU)

Subjects
[SDV]Life Sciences [q-bio], Cell, Parallel plate rheometer, Pharmaceutical Science, Medicine (miscellaneous), 02 engineering and technology, Applied Microbiology and Biotechnology, Cell membrane, Nanotechnology, Cytoskeleton, Internalization, Magnetite Nanoparticles, media_common, 0303 health sciences, Single cell rheology, 021001 nanoscience & nanotechnology, Endocytosis, medicine.anatomical_structure, Magnetic nanoparticles, Molecular Medicine, Single-Cell Analysis, 0210 nano-technology, Rheology, Shear Strength, Biotechnology, Endosome, media_common.quotation_subject, Biomedical Engineering, Bioengineering, Endosomes, 03 medical and health sciences, Microscopy, Electron, Transmission, Medical technology, medicine, Humans, R855-855.5, Nano-bio interface, 030304 developmental biology, Research, Cell Membrane, Actin cytoskeleton, Elasticity, Biophysics, Nanoparticles, Stress, Mechanical, Lysosomes, TP248.13-248.65
Abstract

Background The interactions between nanoparticles and the biological environment have long been studied, with toxicological assays being the most common experimental route. In parallel, recent growing evidence has brought into light the important role that cell mechanics play in numerous cell biological processes. However, despite the prevalence of nanotechnology applications in biology, and in particular the increased use of magnetic nanoparticles for cell therapy and imaging, the impact of nanoparticles on the cells’ mechanical properties remains poorly understood. Results Here, we used a parallel plate rheometer to measure the impact of magnetic nanoparticles on the viscoelastic modulus G*(f) of individual cells. We show how the active uptake of nanoparticles translates into cell stiffening in a short time scale ( Conclusions Overall, this work evidences that magnetic nanoparticle internalization, coupled to cytoskeleton remodeling, contributes to a change in the cell mechanical properties within minutes of their initial contact, leading to an increase in cell rigidity. This effect appears to be transient, reduced after hours and disappearing 24 h after the internalization has taken place.

Published
2020
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