Mechanotransduction: from Cell Surface to Nucleus

NICOLAS BORGHI

How our cells respond to their mechanical environment?

We propose an approach using quantitative fluorescence microscopy and genetic engineering for responses from the molecule to the tissue.

Keywords: mechanotransduction, cell adhesion, cell migration, microscopy, biosensors, biophysics

+33 (0)157278041 nicolas.borghi(at)ijm.fr

In multicellular organisms, cells generate and undergo mechanical forces that propagate throughout the organism. These forces can determine the shape of tissues and organs, and regulate genetic programs. However, the molecular mechanisms of the transmission of mechanical forces and their transduction into biochemical signals are poorly understood.

Our project focuses on the macromolecular complexes that transmit and transduce these mechanical signals within and between cells, and the cellular functions that depend on them. We are interested in plasma membrane adhesion receptors, nuclear envelope transmembrane complexes and their functions in cell adhesion, migration, proliferation and transcriptional activity.

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To address this goal, we develop and use genetically encoded biosensors and advanced microscopy and micromanipulation methods on cell culture model systems. This combination allows us to dynamically and quantitatively control and measure the behavior of protein complexes and cells in a wide range of time and length scales.

Members

Group Leader:

Nicolas BORGHI
Téléphone : +33 (0)157278041
nicolas.borghi [at] ijm.fr

Members:

Nicolas	AUDUGE	Photonic microscopy engineer
Maïté	COPPEY	Emeritus Researcher
Philippe	GIRARD	Lecturer-researcher
Louis	LAURENT	PhD Student
Thomas	GERMIER	Postdoc
Hugo	LACHUER	Postdoc
Mariia	BALATSKAIA	Postdoc

Selected Publications

1: Déjardin T, Carollo PS, Sipieter F, Davidson PM, Seiler C, Cuvelier D, Cadot, B, Sykes C, Gomes ER, Borghi N. Nesprins are mechanotransducers that discriminate epithelial-mesenchymal transition programs. J Cell Biol. 2020 Oct 5;219(10):e201908036. doi: 10.1083/jcb.201908036. PMID: 32790861; PMCID: PMC7659719.

2: Davidson PM, Battistella A, Déjardin T, Betz T, Plastino J, Borghi N, Cadot, B, Sykes C. Nesprin-2 accumulates at the front of the nucleus during confined. cell migration. EMBO Rep. 2020 Jul 3;21(7):e49910. doi: 10.15252/embr.201949910. Epub 2020 May 17. PMID: 32419336; PMCID: PMC7332974.

3: Audugé N, Padilla-Parra S, Tramier M, Borghi N, Coppey-Moisan M. Chromatin condensation fluctuations rather than steady-state predict chromatin accessibility. Nucleic Acids Res. 2019 Jul 9;47(12):6184-6194. doi: 10.1093/nar/gkz373. PMID: 31081027; PMCID: PMC6614833.

4: De Pascalis C, Pérez-González C, Seetharaman S, Boëda B, Vianay B, Burute M, Leduc C, Borghi N, Trepat X, Etienne-Manneville S. Intermediate filaments control collective migration by restricting traction forces and sustaining cell-cell contacts. J Cell Biol. 2018 Sep 3;217(9):3031-3044. doi: 10.1083/jcb.201801162. Epub 2018 Jul 6. PMID: 29980627; PMCID: PMC6122997.

5: Gayrard C, Bernaudin C, Déjardin T, Seiler C, Borghi N. Src- and confinement- dependent FAK activation causes E-cadherin relaxation and β-catenin activity. J Cell Biol. 2018 Mar 5;217(3):1063-1077. doi: 10.1083/jcb.201706013. Epub 2018 Jan 8. PMID: 29311227; PMCID: PMC5839785.

6: Sarangi BR, Gupta M, Doss BL, Tissot N, Lam F, Mège RM, Borghi N, Ladoux B. Coordination between Intra- and Extracellular Forces Regulates Focal Adhesion. Dynamics. Nano Lett. 2017 Jan 11;17(1):399-406. doi: 10.1021/acs.nanolett.6b04364. Epub 2016 Dec 23. PMID: 27990827; PMCID: PMC5423523.

7: Liu Z, Bun P, Audugé N, Coppey-Moisan M, Borghi N. Vinculin head-tail interaction defines multiple early mechanisms for cell substrate rigidity sensing. Integr Biol (Camb). 2016 Jun 13;8(6):693-703. doi: 10.1039/c5ib00307e. Epub 2016 May 11. PMID: 27169142.

8: Lowndes M, Rakshit S, Shafraz O, Borghi N, Harmon RM, Green KJ, Sivasankar S, Nelson WJ. Different roles of cadherins in the assembly and structural integrity of the desmosome complex. J Cell Sci. 2014 May 15;127(Pt 10):2339-50. doi: 10.1242/jcs.146316. Epub 2014 Mar 7. PMID: 24610950; PMCID: PMC4021477.

9: Borghi N, Sorokina M, Shcherbakova OG, Weis WI, Pruitt BL, Nelson WJ, and Alexander R. Dunn. E-cadherin is under constitutive actomyosin-generated tension that is increased at cell-cell contacts upon externally applied stretch. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12568-73. doi: 10.1073/pnas.1204390109. Epub 2012 Jul 16. Erratum in: Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):19034. PMID: 22802638; PMCID: PMC3411997.

10: Borghi N, Lowndes M, Maruthamuthu V, Gardel ML, Nelson WJ. Regulation of cell motile behavior by crosstalk between cadherin- and integrin-mediated adhesions. Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13324-9. doi: 10.1073/pnas.1002662107. Epub 2010 Jun 21. PMID: 20566866; PMCID: PMC2922157.

All the publications since 2017

Publications

Cicero, J., Trouvilliez, S., Palma, M., Ternier, G., Decoster, L., Happernegg, E., Barois, N., Van Outryve, A., Dehouck, L., Bourette, R. P., Adriaenssens, E., Lagadec, C., Tarhan, C. M., Collard, D., Souguir, Z., Vandenhaute, E., Maubon, G., Sipieter, F., Borghi, N., … Toillon, R.-A. (2023). ProNGF promotes brain metastasis through TrkA/EphA2 induced Src activation in triple negative breast cancer cells. Experimental Hematology & Oncology, 12(1), 104. https://doi.org/10.1186/s40164-023-00463-6

Donker, L., Houtekamer, R., Vliem, M., Sipieter, F., Canever, H., Gómez-González, M., Bosch-Padrós, M., Pannekoek, W.-J., Trepat, X., Borghi, N., & Gloerich, M. (2022). A mechanical G2 checkpoint controls epithelial cell division through E-cadherin-mediated regulation of Wee1-Cdk1. Cell Reports, 41(2), 111475. https://doi.org/10.1016/j.celrep.2022.111475

Sipieter, F., Laurent, L., Girard, P. P., & Borghi, N. (2022). Molecular tension microscopy of the LINC complex in live cells. STAR Protocols, 3(3), 101538. https://doi.org/10.1016/j.xpro.2022.101538

Leroy, O., van Leen, E., Girard, P., Villedieu, A., Hubert, C., Bosveld, F., Bellaïche, Y., & Renaud, O. (2022). Multi-view confocal microscopy enables multiple organ and whole organism live-imaging. Development (Cambridge, England), 149(4), dev199760. https://doi.org/10.1242/dev.199760

Sipieter, F., Laurent, L., & Borghi, N. (2021). Nesprins mechanically discriminate between distinct epithelium-to-mesenchyme transitions. Medecine Sciences: M/S, 37(11), 984–986. https://doi.org/10.1051/medsci/2021132

Roebroek, T., Vandenberg, W., Sipieter, F., Hugelier, S., Stove, C., Zhang, J., & Dedecker, P. (2021). Simultaneous readout of multiple FRET pairs using photochromism. Nature Communications, 12(1), 2005. https://doi.org/10.1038/s41467-021-22043-0

Atlas, Y., Gorin, C., Novais, A., Marchand, M. F., Chatzopoulou, E., Lesieur, J., Bascetin, R., Binet-Moussy, C., Sadoine, J., Lesage, M., Opsal-Vital, S., Péault, B., Monnot, C., Poliard, A., Girard, P., Germain, S., Chaussain, C., & Muller, L. (2021). Microvascular maturation by mesenchymal stem cells in vitro improves blood perfusion in implanted tissue constructs. Biomaterials, 268, 120594. https://doi.org/10.1016/j.biomaterials.2020.120594

Aladin, D. M. K., Chu, Y. S., Shen, S., Robinson, R. C., Dufour, S., Viasnoff, V., Borghi, N., & Thiery, J. P. (2021). Extracellular domains of E-cadherin determine key mechanical phenotypes of an epithelium through cell- and non-cell-autonomous outside-in signaling. PloS One, 16(12), e0260593. https://doi.org/10.1371/journal.pone.0260593

Déjardin, T., Carollo, P. S., Sipieter, F., Davidson, P. M., Seiler, C., Cuvelier, D., Cadot, B., Sykes, C., Gomes, E. R., & Borghi, N. (2020). Nesprins are mechanotransducers that discriminate epithelial-mesenchymal transition programs. The Journal of Cell Biology, 219(10), e201908036. https://doi.org/10.1083/jcb.201908036

Davidson, P. M., Battistella, A., Déjardin, T., Betz, T., Plastino, J., Borghi, N., Cadot, B., & Sykes, C. (2020). Nesprin-2 accumulates at the front of the nucleus during confined cell migration. EMBO Reports, 21(7), e49910. https://doi.org/10.15252/embr.201949910

Umana-Diaz, C., Pichol-Thievend, C., Marchand, M. F., Atlas, Y., Salza, R., Malbouyres, M., Barret, A., Teillon, J., Ardidie-Robouant, C., Ruggiero, F., Monnot, C., Girard, P., Guilluy, C., Ricard-Blum, S., Germain, S., & Muller, L. (2020). Scavenger Receptor Cysteine-Rich domains of Lysyl Oxidase-Like2 regulate endothelial ECM and angiogenesis through non-catalytic scaffolding mechanisms. Matrix Biology: Journal of the International Society for Matrix Biology, 88, 33–52. https://doi.org/10.1016/j.matbio.2019.11.003

Audugé, N., Padilla-Parra, S., Tramier, M., Borghi, N., & Coppey-Moisan, M. (2019). Chromatin condensation fluctuations rather than steady-state predict chromatin accessibility. Nucleic Acids Research, 47(12), 6184–6194. https://doi.org/10.1093/nar/gkz373

De Pascalis, C., Pérez-González, C., Seetharaman, S., Boëda, B., Vianay, B., Burute, M., Leduc, C., Borghi, N., Trepat, X., & Etienne-Manneville, S. (2018). Intermediate filaments control collective migration by restricting traction forces and sustaining cell-cell contacts. The Journal of Cell Biology, 217(9), 3031–3044. https://doi.org/10.1083/jcb.201801162

Gayrard, C., & Borghi, N. (2018). How mechanotransduction between adhesion complexes results in β-catenin pathway activation. Medecine Sciences: M/S, 34(6–7), 506–508. https://doi.org/10.1051/medsci/20183406004

Gayrard, C., Bernaudin, C., Déjardin, T., Seiler, C., & Borghi, N. (2018). Src- and confinement-dependent FAK activation causes E-cadherin relaxation and β-catenin activity. The Journal of Cell Biology, 217(3), 1063–1077. https://doi.org/10.1083/jcb.201706013

Sarangi, B. R., Gupta, M., Doss, B. L., Tissot, N., Lam, F., Mège, R.-M., Borghi, N., & Ladoux, B. (2017). Coordination between Intra- and Extracellular Forces Regulates Focal Adhesion Dynamics. Nano Letters, 17(1), 399–406. https://doi.org/10.1021/acs.nanolett.6b04364

Review

Book chapter

Theses

2017: Charlène Gayrard – Mécanotransduction au complexe E-cadhérine/bêta-caténine lors de la transition épithélio-mésenchymateuse.
2019: Pietro Salvatore Carollo – The LINC complex is a mechanotransducer that regulates catenin signalling dyring epithelial-mesenchymal transitions.
2021: Helena Canever – Regulation of epithelial migration by cell adhesions: roles of vinculin.
Ongoing: Louis Laurent.

Mechanotransduction: from Cell Surface to Nucleus

NICOLAS BORGHI

Research