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
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
Membres de l’équipe :
| ANGER | Lucas | Ingénieur en biologie |
| BARAI | Amlan | Postdoctorant |
| D’ALESSANDRO | Joseph | Chercheur |
| DE BECO | Simon | Enseignant-chercheur |
| DELACOUR | Delphine | Chercheur |
| DUBEY | Sushil | Postdoctorant |
| FARDIN | Marc-Antoine | Chercheur |
| LADOUX | Benoît | Chercheur |
| MEGE | René-Marc | Chercheur |
| DANG | Tien | Ingénieure en biologie |
| PENETI | Sudheer Kumar | Doctorant |
| ROSSE | Carine | chercheur invitée |
| SCHONIT | Andreas | Doctorant |
| SHEN | Yuan | Postdoctorant |
| SOLEILHAC | Matis | Doctorant |
| WODRASCKA | Fanny | Doctorante |
| WU | Huiqiong | Postdoctorante |
| XI | Wang | Chercheur |
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
Sonam, S., Balasubramaniam, L., Lin, SZ. et al. Mechanical stress driven by rigidity sensing governs epithelial stability. Nat. Phys. (2022). https://doi.org/10.1038/s41567-022-01826-2
d’Alessandro J, Barbier-Chebbah A, Voituriez R, Ladoux B. Les cellules, « Petits Poucets » des tissus vivants [Cells as « Tom Thumbs » of living tissues]. Med Sci (Paris). 2022 Nov;38(11):861-863. French. doi:10.1051/medsci/2022138. Epub 2022 Nov 30. PMID: 36448887.
Kabla A, Ladoux B, Di Meglio JM. Tissue mechanics. Eur Phys J E Soft Matter. 2022 Nov 9;45(11):90. doi: 10.1140/epje/s10189-022-00240-z. PMID: 36350421.
Petracchini S, Hamaoui D, Doye A, Asnacios A, Fage F, Vitiello E, Balland M, Janel S, Lafont F, Gupta M, Ladoux B, Gilleron J, Maia TM, Impens F, Gagnoux- Palacios L, Daugaard M, Sorensen PH, Lemichez E, Mettouchi A. Optineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division. Nat Commun. 2022 Oct 13;13(1):6059. doi: 10.1038/s41467-022-33803-x. PMID: 36229487; PMCID: PMC9561704.
Glentis A, Blanch-Mercader C, Balasubramaniam L, Saw TB, d’Alessandro J, Janel S, Douanier A, Delaval B, Lafont F, Lim CT, Delacour D, Prost J, Xi W, Ladoux B. The emergence of spontaneous coordinated epithelial rotation on cylindrical curved surfaces. Sci Adv. 2022 Sep 16;8(37):eabn5406. doi:10.1126/sciadv.abn5406. Epub 2022 Sep 14. PMID: 36103541; PMCID: PMC9473582.
Balasubramaniam L, Mège RM, Ladoux B. Active forces modulate collective behaviour and cellular organization. C R Biol. 2021 Dec 20;344(4):325-335. doi:10.5802/crbiol.65. PMID: 35787604.
Zakharova VV, Magnitov MD, Del Maestro L, Ulianov SV, Glentis A, Uyanik B, Williart A, Karpukhina A, Demidov O, Joliot V, Vassetzky YS, Mège RM, Piel M, Razin SV, Ait-Si-Ali S. SETDB1 fuels the lung cancer phenotype by modulating epigenome, 3D genome organization and chromatin mechanical properties. Nucleic Acids Res. 2022 May 6;50(8):4389-4413. doi: 10.1093/nar/gkac234. PMID: 35474385; PMCID: PMC9071401.
Fardin MA, Hautefeuille M, Sharma V. Spreading, pinching, and coalescence: the Ohnesorge units. Soft Matter. 2022 May 4;18(17):3291-3303. doi:10.1039/d2sm00069e. PMID: 35416235.
Doostmohammadi A, Ladoux B. Physics of liquid crystals in cell biology: (Trends in Cell Biology 32, 140-150, 2022). Trends Cell Biol. 2022 Apr;32(4):365. doi: 10.1016/j.tcb.2022.01.010. Epub 2022 Feb 7. Erratum for: Trends Cell Biol. 2022 Feb;32(2):140-150. PMID: 35144883.
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. Modulation of designer biomimetic matrices for optimized differentiated intestinal epithelial cultures. Biomaterials. 2022 Mar;282:121380. doi:10.1016/j.biomaterials.2022.121380. Epub 2022 Jan 18. PMID: 35101742.
Yang YA, Nguyen E, Sankara Narayana GHN, Heuzé M, Fu C, Yu H, Mège RM, Ladoux B, Sheetz MP. Local contractions regulate E-cadherin rigidity sensing. Sci Adv. 2022 Jan 28;8(4):eabk0387. doi: 10.1126/sciadv.abk0387. Epub 2022 Jan 28. PMID: 35089785; PMCID: PMC8797795.
Balasubramaniam L, Mège RM, Ladoux B. Active nematics across scales from cytoskeleton organization to tissue morphogenesis. Curr Opin Genet Dev. 2022 Apr;73:101897. doi: 10.1016/j.gde.2021.101897. Epub 2022 Jan 18. PMID: 35063879. Doostmohammadi A, Ladoux B. Physics of liquid crystals in cell biology. Trends Cell Biol. 2022 Feb;32(2):140-150. doi: 10.1016/j.tcb.2021.09.012. Epub 2021 Oct 27. Erratum in: Trends Cell Biol. 2022 Apr;32(4):365. PMID: 34756501.
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.
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.
Sonam S, Vigouroux C, Jégou A, Romet-Lemonne G, Le Clainche C, Ladoux
B, Mège RM.
Biol Cell.
Cell migration guided by long-lived spatial memory
d’Alessandro J, Barbier-Chebbah A, Cellerin V, Benichou O, Mège RM,
Voituriez R, Ladoux B.
Nat Commun.
Mechanical plasticity in collective cell migration
Jain S, Ladoux B, Mège RM.
Curr Opin Cell Biol.
Ankyrin G organizes membrane components to promote coupling of cell mechanics and glucose uptake
Salvi AM, Bays JL, Mackin SR, Mege RM, DeMali KA
Nat Cell Biol.
EpCAM promotes endosomal modulation of the cortical RhoA zone for epithelial organization
Nat Commun.
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.
Nat. Mater.
Adhesion-mediated heterogeneous actin organization governs apoptotic cell extrusion
Le AP, Rupprecht JF, Mège RM, Toyama Y, Lim CT, Ladoux B.
Nat. Commun.
Living proof of effective defects
Fardin MA & Ladoux B
Nat. Phys.
Ghisleni A, Galli C, Monzo P, Ascione F, Fardin MA, Scita G, Li Q,
Maiuri P, Gauthier NC
Nat Commun.
Migrating Epithelial Monolayer Flows Like a Maxwell Viscoelastic Liquid
Tlili S, Durande M, Gay C, Ladoux B, Graner F, Delanoë-Ayari H.
Phys Rev Lett.
Human Microphysiological Models of Intestinal Tissue and Gut Microbiome
Steinway SN, Saleh J, Koo BK, Delacour D, Kim DH
Front Bioeng Biotechnol.
Caveolae Control Contractile Tension for Epithelia to Eliminate Tumor Cells
Teo JL, Gomez GA, Weeratunga S, Davies EM, Noordstra I, Budnar S,
Katsuno-Kambe H, McGrath MJ, Verma S, Tomatis V, Acharya BR, Balasubramaniam L,Templin RM, McMahon KA, Lee YS, Ju RJ, Stebhens SJ, Ladoux B, Mitchell CA, Collins BM, Parton RG, Yap AS
Dev Cell.
Cell response to substrate rigidity is regulated by active and passive cytoskeletal stress
Doss BL, Pan M, Gupta M, Grenci G, Mège RM, Lim CT, Sheetz M, Voituriez R & Ladoux B
PNAS
Galectin-3 modulates epithelial cell adaptation to stress at the ER- mitochondria interface
Coppin L, Jannin A, Ait Yahya E, Thuillier C, Villenet C, Tardivel M,
Bongiovanni A, Gaston C, de Beco S, Barois N, van Seuningen I, Durand E,
Bonnefond A, Vienne JC, Vamecq J, Figeac M, Vincent A, Delacour D,
Porchet N, Pigny P.
Cell Death Dis.
The role of single-cell mechanical behaviour and polarity in driving collective cell migration
Jain S., Cachoux V.M.L., Narayana G.H.N.S. de Beco S., d’Alessandro J., Cellerin V., Chen T., Heuze M., Marcq P., Mège R.M., Kabla A.J., Lim C.T. & Ladoux B
Nature Physics
Thomas M, Ladoux B, Toyama Y
Curr Biol.
A subtle relationship between substrate stiffness and collective migration of cell clusters
Balcioglua HE, Balasubramaniam L, Stirbat TV, Dossa B, Fardin MA, Mège RM, Ladoux B
Soft Matter
Molecular basis for fluidization of cancer cells
Mège RM
Nature Materials
Bosch-Fortea M, Rodriguez-Fraticelli AE, Herranz G, Hachimi M, Barea MD, Young J, Ladoux B, Martin-Belmonte F
Biomaterials
Myosin II isoforms play distinct roles in adherens junction biogenesis
Heuzé ML, Sankara Narayana GHN, D’Alessandro J, Cellerin V, Dang T, Williams DS, Van Hest JCM, Marcq P, Mège RM, Ladoux B
eLIFE
Sustained Oscillations of Epithelial Cell Sheets
Peyret G, Mueller R, d’Alessandro J, Begnaud S, Marcq P, Mège RM, Yeomans JM, Doostmohammadi A, Ladoux B
Biophysical Journal
Hu S, Grobe H, Guo Z, Wang YH, Doss BL, Pan M, Ladoux B, Bershadsky AD, Zaidel-Bar R
Molecular Biology of the Cell
Nguyen T, Duchesne L, Sankara Narayana GHN, Boggetto N, Fernig DD, Uttamrao Murade C, Ladoux B, Mège RM
Oncogene
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
Large-scale curvature sensing by directional actin flow drives cellular migration mode switching
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
Nature Physics
Yeo MS, Subhash VV, Suda K, Balcıoğlu HE, Zhou S, Thuya WL, Loh XY, Jammula S, Peethala PC, Tan SH, Xie C, Wong FY, Ladoux B, Ito Y, Yang H, Goh BC, Wang L, Yong WP
Cancers (Basel)
Cell shape and substrate stiffness drive actin-based cell polarity
Gupta M, Doss B L, Kocgozlu L, Pan M, Mège R-M, Callan-Jones A, Voituriez R, Ladoux B
Physical Review E
Material approaches to active tissue mechanics
Xi W, Saw TB, Delacour D, Lim CT, Ladoux B
Nature Review Materials
Mechanical forces in cell monolayers
Chen T, Saw TB, Mège RM, Ladoux B
Journal of Cell Science
The irruption of mechanics in the chemistry of life
Mège RM, Ladoux B
Medecine & Sciences (Paris)
Active superelasticity in three-dimensional epithelia of controlled shape
Latorre E, Kale S, Casares L, Gómez-González M, Uroz M, Valon L, Nair RV, Garreta E, Montserrat N, Del Campo A, Ladoux B, Arroyo M, Trepat X
Nature
Kalman Inversion Stress Microscopy
Nier V., Peyret G., d’Alessandro J., Ishihara S., Ladoux B., Marcq P.
Biophysical Journal
Biological Tissues as Active Nematic Liquid Crystals
Collective cell migration without proliferation: density determines cell velocity and wave velocity
Tlili S., Gauquelin E., Li B., Cardoso O., Ladoux B., Delanoë-Ayari H., Graner F.
Royal Society Open Science
Seddiki R., Sankara Narayana G. H. N., Strale P-O., Balcioglu H.E., Peyret G., Yao M., Le A.P., Lim C. T., Yan J., Ladoux B. & Mège R.M.
Molecular Biology of the Cell
Mechanobiology of collective cell behaviours
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 Voituriez, Philippe Marcq
Sorbonne Université, Paris
Sylvie Hénon
Laboratoire Matière et Systèmes Complexes, Université de Paris
Philippe Chavrier, Christophe Lamaze, Jacques 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
13/04/2023 – Postdoc offer on cell and tissue mechanics
04/04/2022 – Postdoctoral position in cell division during epithelial morphogenesis
17/02/2022 – Post-doc
01/12/2021 – Post-doc -Dead or Alive project (ERC)
