.

Cell Adhesion and Mechanics

BENOIT LADOUX & RENÉ MARC MÈGE

Mechanical constraints and force transmission play an essential role in multicellular living organisms They are regulating basic biological processes such as morphogenesis, tumor metastasis and tissue repair. Cell adhesions, coupled to the contractile cytoskeleton, are major sites of force transmission in cells. This mechanical coupling which enables cells to sense, signal, and respond to physical changes in the environment, has however been largely understudied. In this context, we are studying the cooperation between adhesion, mechanical and biochemical signaling for the adaptation of living cells to changes in their physical environment at various scales, from single molecules to tissues.

Keywords: mechanobiology, mechanosensing, epithelia homeostasis, collective cell migration, microfabrication, biophysics, cell extrusion, tissue mechanics

+33 (0)157278071 /  +33 (0)157278067     benoit.ladoux(at)ijm.fr  /  rene-marc.mege(at)ijm.fr     @BLadoux     @ReneMege    

https://ladoux-mege-lab.cnrs.fr/

AT THE SINGLE CELLS LEVEL

We study force sensing and mechanotransduction at integrin-mediated cell-extracellular matrix and cadherin-mediated cell-cell adhesions. To answer these questions, we have developed single cells and cell doublets models allowing a tight control of cell-matrix and cell-adhesion formation in a physically and mechanically defined microenvironment. Coupled with advanced microscopy, microforce sensor devices and classical cell biology, these approaches allow us to determine the molecular mechanisms that control cell adhesion and cytoskeleton remodeling, as well as cell shape and migration and their adaptation to environment compliance as well as to cytoskeleton visco-elastic properties and cell’s internal tension generated by myosin motors.

 

AT THE CELL ASSEMBLIES LEVEL

 

We study the collective behavior of cells in epithelial sheets, in the context of tissue homeostasis and wound healing. To answer these questions, we developing microfabricated tools   and biophysical tools to measure and control the mechanical properties and topology of cell’s microenvironment. These tools are combined with molecular approaches, advanced techniques in light microscopy, image analysis and modeling to study the influence of physical properties of the environment on the organization of epithelial layers, collective cell migration, single and collective cell polarization, cell division and cell extrusion. We are characterizing how physical constraints can lead to emergent dynamical and mechanical properties of various epithelial tissues.

 

 

AT THE TISSUES AND ORGANOID LEVEL

 

We study how more complex epithelial tissues formed of mixed populations of cells (normal/adhesion deficient, normal/cancer, differentiation/stem cells) facing homogeneous and heterogeneous substrates (extracellular matrix chemistry, rigidity, geometry and topography), regulate homeostasis, segregate and/or auto assemble. Our aims are to determine i) how physical constraints of the microenvironment modulate mechanical properties of epithelial cells and tissues, ii) how they direct a variety of cell behaviors including stem cell proliferation, cell extrusion or delamination, cell migration, differentiation, and polarity, and iii) how they impact on the morphogenesis normal epithelial tissue, as well as the pathological development of intestinal rare diseases. Biomimetic substrates coupled to high resolution imaging and biochemistry are instrumental to reach these goals.

 

Group Leaders:

Benoît LADOUX
Téléphone : +33 (0)157278071 / Email : benoit.ladoux (at) ijm.fr

René-Marc MÈGE
Téléphone : +33 (0)157278067 / Email : rene-marc.mege (at) ijm.fr

 

Members:

ANGER Lucas Biological engineer
BARAI Amlan Postdoc
CELLERIN Victor PhD Student
D’ALESSANDRO Joseph Researcher
DE BECO Simon Researcher
DELACOUR Delphine Researcher
DUBEY Sushil Postdoc
FARDIN Marc-Antoine Researcher
FRENOY Olivia Biological engineer
GUEVARA GARCIA Amaris Postdoc
KUONY Alison Postdoc
LADOUX Benoît Researcher
MEGE René-Marc Researcher
MERCIER Barbara PhD Student
NGUYEN Tien Biological engineer
PENETI Sudheer Kumar PhD Student
SCHONIT Andreas PhD Student
SOLEILHAC Matis PhD Student
WODRASCKA Fanny PhD Student
WU Huiqiong Postdoc
XI Wang Researcher

Balasubramaniam L, Doostmohammadi A, Saw TB, Narayana GHNS, Mueller R, Dang T, Thomas M, Gupta S, Sonam S, Yap AS, Toyama Y, Mège RM, Yeomans JM, Ladoux B. Investigating the nature of active forces in tissues reveals how contractile cells can form extensile monolayers. Nat Mater. 2021 Aug;20(8):1156-1166. doi: 10.1038/s41563-021-00919-2. Epub 2021 Feb 18. Erratum in: Nat Mater. 2021 Mar 9;: PMID: 33603188; PMCID: PMC7611436.

Gaston C, De Beco S, Doss B, Pan M, Gauquelin E, D’Alessandro J, Lim CT, Ladoux B, Delacour D. EpCAM promotes endosomal modulation of the cortical RhoA zone for epithelial organization. Nat Commun. 2021 Apr 13;12(1):2226. doi: 10.1038/s41467-021-22482-9. PMID: 33850145; PMCID: PMC8044225.

Jain S, Cachoux VML, Narayana GHNS, de Beco S, D’Alessandro J, Cellerin V, Chen T, Heuzé ML, Marcq P, Mège RM, Kabla AJ, Lim CT, Ladoux B. The role of single cell mechanical behavior and polarity in driving collective cell migration. Nat Phys. 2020 Jul;16(7):802-809. doi: 10.1038/s41567-020-0875-z. Epub 2020 May 4. PMID: 32641972; PMCID: PMC7343533.

Le AP, Rupprecht JF, Mège RM, Toyama Y, Lim CT, Ladoux B. Adhesion-mediated heterogeneous actin organization governs apoptotic cell extrusion. Nat Commun. 2021 Jan 15;12(1):397. doi: 10.1038/s41467-020-20563-9. PMID: 33452264; PMCID: PMC7810754.

Doss BL, Pan M, Gupta M, Grenci G, Mège RM, Lim CT, Sheetz MP, Voituriez R, Ladoux B. Cell response to substrate rigidity is regulated by active and passive cytoskeletal stress. Proc Natl Acad Sci U S A. 2020 Jun 9;117(23):12817-12825.
doi: 10.1073/pnas.1917555117. Epub 2020 May 22. PMID: 32444491; PMCID: PMC7293595.

Heuzé ML, Sankara Narayana GHN, D’Alessandro J, Cellerin V, Dang T, Williams DS, Van Hest JC, Marcq P, Mège RM, Ladoux B. Myosin II isoforms play distinct roles in <i>adherens</i> junction biogenesis. Elife. 2019 Sep 5;8:e46599. doi: 10.7554/eLife.46599. PMID: 31486768; PMCID: PMC6756789.

Chen T, Callan-Jones A, Fedorov E, Ravasio A, Brugués A, Ong HT, Toyama Y, Low BC, Trepat X, Shemesh T, Voituriez R, Ladoux B. Large-scale curvature sensing by directional actin flow drives cellular migration mode switching. Nat Phys. 2019 Apr;15:393-402. doi: 10.1038/s41567-018-0383-6. Epub 2019 Jan 21. PMID: 30984281; PMCID: PMC6456019.

Seddiki R, Narayana GHNS, Strale PO, Balcioglu HE, Peyret G, Yao M, Le AP, Teck Lim C, Yan J, Ladoux B, Mège RM. Force-dependent binding of vinculin to α-catenin regulates cell-cell contact stability and collective cell behavior.
Mol Biol Cell. 2018 Feb 15;29(4):380-388. doi: 10.1091/mbc.E17-04-0231. Epub 2017 Dec 27. PMID: 29282282; PMCID: PMC6014167.

Saw TB, Doostmohammadi A, Nier V, Kocgozlu L, Thampi S, Toyama Y, Marcq P, Lim CT, Yeomans JM, Ladoux B. Topological defects in epithelia govern cell death and extrusion. Nature. 2017 Apr 12;544(7649):212-216.
Abstract

Salomon J, Gaston C, Magescas J, Duvauchelle B, Canioni D, Sengmanivong L, Mayeux A, Michaux G, Campeotto F, Lemale J, Viala J, Poirier F, Minc N, Schmitz J, Brousse N, Ladoux B, Goulet O, Delacour D. Contractile forces at tricellular contacts modulate epithelial organization and monolayer integrity. Nat Commun. 2017 Jan 13;8:13998.
Abstract

Local contractions regulate E-cadherin rigidity sensing

Yang YA, Nguyen E, Sankara Narayana GHN, Heuzé M, Fu C, Yu H, Mège RM, Ladoux B, Sheetz MP

Sci Adv.

 

Active nematics across scales from cytoskeleton organization to tissue morphogenesis

Balasubramaniam L, Mège RM, Ladoux B

Curr Opin Genet Dev.

 

Modulation of designer biomimetic matrices for optimized differentiated intestinal epithelial cultures

Xi W, Saleh J, Yamada A, Tomba C, Mercier B, Janel S, Dang T, Soleilhac M, Djemat A, Wu H, Romagnolo B, Lafont F, Mège RM, Chen Y, Delacour D

Biomaterials.

 

Physics of liquid crystals in cell biology

Doostmohammadi A, Ladoux B

Trends Cell Biol.

 

Direct measurement of near-nano-Newton forces developed by self-organizing actomyosin fibers bound α-catenin

Sonam S, Vigouroux C, Jégou A, Romet-Lemonne G, Le Clainche C, Ladoux
B, Mège RM.

Biol Cell.

 

 

Molecular basis for fluidization of cancer cells

Mège RM

Nature Materials

 

Influence of proliferation on the motions of epithelial monolayers invading adherent strips

Gauquelin E, Tlili S, Gay C, Peyret G, Mège RM, Fardin MA, Ladoux B

Soft Matter

 

Mechanobiology of collective cell behaviours

Ladoux B & Mège RM

Nature Reviews Molecular Cell Biology

 

Spindle pole cohesion requires glycosylation-mediated localization of NuMA

Magescas J., Sengmanivong L., Viau A., Mayeux A., Dang T., Burtin M., Nilsson U.J., Leffler H., Poirier F., Terzi F., Delacour D.

Scientific Report

 

A phenomenological model of cell-cell adhesion mediated by cadherins

Mancini S, Mège RM, Sarels B, Strale PO.

J Math Biol.

 

Front-Rear Polarization by Mechanical Cues: From Single Cells to Tissues

Ladoux B, Mège RM, Trepat X.

Trends Cell Biol.

 

Plasticity of the brush border -
the yin and yang of intestinal homeostasis

Feb 3, 2016

Delacour D, Salomon J, Robine S, Louvard D.
Nat Rev Gastroenterol Hepatol.

Early Passage
Dependence of Mesenchymal Stem Cell Mechanics Influences Cellular Invasion and
Migration

Nov 18, 2015

Spagnol ST, Lin WC, Booth EA, Ladoux B, Lazarus HM, Dahl KN.
Ann Biomed Eng.

 

Protrusive waves guide 3D cell migration along nanofibers

Nov 9, 2015

Guetta-Terrier C, Monzo P, Zhu J, Long H, Venkatraman L, Zhou Y, Wang P, Chew SY, Mogilner A, Ladoux B, Gauthier NC.
J Cell Biol.

 

Actin-Based Transport Adapts Polarity Domain Size to Local Cellular Curvature

Oct 19, 2015

Bonazzi D, Haupt A, Tanimoto H, Delacour D, Salort D, Minc N.
Curr Biol.

The mechanotransduction machinery at work at adherens junctions

Oct 5, 2015

Ladoux B, Nelson WJ, Yan J, Mège RM.
Integr Biol (Camb)

Regulation of epithelial cell organization by tuning cell-substrate adhesion

Ravasio A, Le AP, Saw TB, Tarle V, Ong HT, Bertocchi C, Mège RM, Lim CT, Gov NS, Ladoux B.

Integr Biol (Camb).

 

A Chlamydia effector recruits CEP170 to reprogram host microtubule organization

Sep 15, 2015

Dumoux M, Menny A, Delacour D, Hayward RD.
J Cell Sci.

The formation of ordered nanoclusters controls cadherin anchoring to actin and cell-cell contact fluidity

Jul 20, 2015

Strale PO, Duchesne L, Peyret G, Montel L, Nguyen T, Png E, Tampé R, Troyanovsky S, Hénon S, Ladoux B, Mège RM.
J Cell Biol.

Heterogeneous flow kinematics of cellulose nanofibril suspensions under shear

Jun 28, 2015

Martoïa F, Perge C, Dumont PJ, Orgéas L, Fardin MA, Manneville S, Belgacem MN.
Soft Matter.

Adaptive rheology and ordering of cell cytoskeleton govern matrix rigidity sensing

Jun 25, 2015

Gupta M, Sarangi BR, Deschamps J, Nematbakhsh Y, Callan-Jones A, Margadant F, Mège RM, Lim CT, Voituriez R, Ladoux B.
Nat Commun.

 

In vivo examination of the cortical cytoskeleton in multiciliated cells using electron tomography

May 27, 2015

Clare DK, Dumoux M, Delacour D.
Methods Cell Biol

Mechanical link between durotaxis, cell polarity and anisotropy during cell migration

Aubry D, Gupta M, Ladoux B, Allena R.

Phys Biol.

 

Overexpression of galectin-7 in mouse epidermis leads to loss of cell junctions and defective skin repair

Mar 5, 2015

Gendronneau G, Sanii S, Dang T, Deshayes F, Delacour D, Pichard E, Advedissian T, Sidhu SS, Viguier M, Magnaldo T, Poirier F.
PLoS One

High-resolution imaging of cellular processes across textured surfaces using an indexed-matched elastomer

Mar 1, 2015

Ravasio A, Vaishnavi S, Ladoux B, Viasnoff V.
Acta Biomater.

Mechanics of epithelial closure over non-adherent environments

Jan 22, 2015

Vedula SR, Peyret G, Cheddadi I, Chen T, Brugués A, Hirata H, Lopez-Menendez H, Toyama Y, de Almeida LN, Trepat X, Lim CT, Ladoux B.
Nat Commun.

Micropillar substrates: a tool for studying cell mechanobiology

Jan 8, 2015

Gupta M, Kocgozlu L, Sarangi BR, Margadant F, Ashraf M, Ladoux B.
Methods Cell Biol.

INTERNATIONAL

Alexandre Kabla
Cambridge University, UK

Xavier Trepat
IBEC, Spain

Alpha Yap
University of Queensland, Australia

Julia Yeomans
Oxford University, UK

Michael Sheetz
Pakorn tony Kanchanawong
Lim chwee Teck
Yusuke Tonama
Yan Jie
Gianluca Grenci
Mechanobiology Institute (MBI), Singapore

NATIONAL:

FRANCE

Raphael VoituriezPhilippe Marcq
Sorbonne Université, Paris

Sylvie Hénon
Laboratoire Matière et Systèmes Complexes, Université de Paris

Philippe ChavrierChristophe LamazeJacques Prost
Institut Curie, Paris 

Olivier Goulet
Hôpital Necker-Enfants Malades, Paris

Yong Chen
Ecole Normale Supérieure, Département de Chimie, Paris

Bénédicte Dalaval
CRBM, Montpellier

 

INTERNAL

Nicolas Borghi
Mechanotransduction: from Cell Surface to Nucleus

Nicolas Minc
Cellular Spatial Organization

Guillaume Romet-Lemonne & Antoine Jégou
Regulation of Actin Assembly Dynamics

.