PHD2023-11

PHD2023-11

Reverse haptotaxis: from reductionist experimentation to mathematical and physical modeling

Host laboratory and collaborators

Olivier Theodoly (LAI) / olivier.theodoly@inserm.fr

Julien Olivier (I2M) / julien.olivier@univ-amu.fr

Cell guidance by anchored molecules, or haptotaxis, is crucial in development, immunology and cancer. Adhesive haptotaxis (guidance by adhesion molecules), and long-range ratchetotaxis (guidance by repetition of asymmetric gradients) are well established for mesenchymal cells such as fibroblasts, but were never reported for amoeboid cells. We recently showed in vitro that amoeboid T lymphocytes orient towards decreasing adhesion gradients, a phenomenon called ‘reverse haptotaxis’ (Luo et al. JCS, 2020), and that they perform reverse ratchetotaxis (in preparation). The mechanisms of these unique phenotypes remain largely unknown. We propose here to use our technologies of optical protein printing to perform controlled reductionist experiments of hapto- and ratcheto-taxis versus variation of microenvironments properties and perturbations of cell functions. These results will be analyzed in regard to mathematical and statistical physics models to decipher quantitatively the mechanisms of atypic directed migration by adhesion cues.

Keywords

Directed cell migration, cell adhesion, haptotaxis, ratchetotaxis, integrins, microfluidics, protein printing

Objectives

The goal of the PhD is to decipher the mechanisms of reverse hapto- and ratcheto-taxis The candidate will perform model experiments with human T lymphocytes on substrates patterned by integrin ligands. The tight control of patterns geometries (crenels, gradients, asymmetric sawteeth) accessible by our techniques of optical protein printing combined with quantitative analysis of migration phenotypes will allow a direct comparison of experimental data with our recently developed mathematical models (inspired by Ziegert et al., 2013) and with new theoretical models initiated during this project.

Proposed approach (experimental / theoretical / computational)

The approaches developed by the PhD candidate will be primarily experimental and supervised by the experimentalist supervisor, O. Theodoly. However, the design and results of the experiments will be discussed with the theoreticians to match the conditions of the modeling approaches. The PhD candidate will not develop the theoretical models but will be apply them to its experimental results under the supervision of the mathematician supervisor, J.Olivier. We will also discuss our results with physicists theoretician from the centuri community that are interested in modeling of reverse ratchetotaxis by different and complementary approaches to the phase field models.

Interdisciplinarity

The project is an original combination of expertise from experimentalists, mathematicians and physical theoreticians that have not worked altogether yet. This highly interdisciplinary project aims at creating and reinforcing a new interdisciplinary collaboration in the CENTURI community.

Expected profile

The candidate should have experience in cell biology and/or biophysics, and a marked interest for microtechnologies and quantitative analysis with theoretical models.

Is this project the continuation of an existing project or an entirely new one? In the case of an existing project, please explain the links between the two projects

A part of the project is a continuation: a phase field approach was recently developed by Julien Olivier to model adhesive haptotaxis and experiments are required to confront with model predictions. Another part of the project is new. Ratchetotaxis of amoeboid cells has never been adressed in the literature and our preliminary results reveal new phenotypes that deserve precise analysis by statistical physics to unravel the mechanisms.

2 to 5 references related to the project

  • Luo, X.; Noray, V. S. de; Aoun, L.; Biarnes-Pelicot, M.; Strale, P.-O.; Studer, V.; Valignat, M.-P.; Theodoly, O. Lymphocytes Perform Reverse Adhesive Haptotaxis Mediated by LFA-1 Integrins. J. Cell Sci. 2020, 133 (16). https://doi.org/10.1242/jcs.242883
  • Caballero, D; Comelles, J; Piel, M; Voituriez, R; Riveline, D. Ratchetaxis: Long-Range Directed Cell Migration by Local Cues. Trends in cell Biology 2015 (25) DOI10.1016/j.tcb.2015.10.009
  • Ziebert, F and Aranson, I.S. Effects of Adhesion Dynamics and Substrate Compliance on the Shape and Motility of Crawling Cells. Plos One 2013, 8 (5). 10.1371/journal.pone.0064511

3 main publications from each PI over the last 5 years

Olivier Theodoly

  • Seveau de Noray, V., F. Manca, I. Mainil, A. Remson, M. Biarnes-Pelicot, S. Gabriele, M.-P. Valignat, and O. Theodoly. 2022. Keratocytes migrate against flow with a roly-poly-like mechanism. Proceedings of the National Academy of Sciences. 119:e2210379119
  • Luo, X.; Noray, V. S. de; Aoun, L.; Biarnes-Pelicot, M.; Strale, P.-O.; Studer, V.; Valignat, M.-P.; Theodoly, O. Lymphocytes Perform Reverse Adhesive Haptotaxis Mediated by LFA-1 Integrins. J. Cell Sci. 2020, 133 (16). https://doi.org/10.1242/jcs.242883
  • Aoun, L.; Farutin, A.; Garcia-Seyda, N.; Nègre, P.; Rizvi, M. S.; Tlili, S.; Song, S.; Luo, X.; Biarnes-Pelicot, M.; Galland, R.; Sibarita, J.-B.; Michelot, A.; Hivroz, C.; Rafai, S.; Valignat, M.-P.; Misbah, C.; Theodoly, O. Amoeboid Swimming Is Propelled by Molecular Paddling in Lymphocytes. Biophys. J. 2020, 119 (6), 1157–1177. https://doi.org/10.1016/j.bpj.2020.07.033.

Julien Olivier

  • Peter Sollich, Julien Olivier, Didier Bresch. Aging and linear response in the Hébraud–Lequeux model for amorphous rheology. Journal of Physics A: Mathematical and Theoretical, 2017, 50 (16), ⟨10.1088/1751-8121/aa6261⟩. ⟨hal-01760557⟩
  • Cell motility in confinement: a computational model for the shape of the cell
    Florence Hubert, Meriem Jedouaa, Imene Khames, Julien Olivier, Olivier Theodoly and Ariane Trescases
    ESAIM: ProcS, 55 (2016) 148-166. https://doi.org/10.1051/proc/201655166
  • Probing relevant ingredients in mean-field approaches for the athermal rheology of yield stress materials.
    Puosi, Francesco and Olivier, Julien and Martens, Kirsten, Soft Matter (2015), 11 (38) pp.7639--7647

 

 

 

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