Research topics

Cancer mechanics


Single cell thermography

Cell mechanics & tribology



Cancer mechanics

Despite deeper understanding of cancer metabolism, 90% of experimental drugs fail in clinical studies, mostly due to lack of efficacy. This stems from the lack of predictability of in vitro and in vivo models that are used to design generic drugs at preclinical stages, and from the limited histophysiological clues that can guide clinicians in adapting the generic therapy to each patient. At the same time, it is now well established that the mechanical properties of tumours control their physiology. Tumours have a complex structure containing several cell types, connected together by transmembrane bonds or extracellular matrix interactions. From a mechanical point of view, this structure can be recapitulated as an elastic frame invaded by biological fluids, with a behaviour resembling that of poroelastic materials. As such tumours are comparable to sponges soaked with biological fluids, where permeability drives resistance to fluid flow and cohesivity dictates the elasticity of the skeletal frame. The role of elasticity and permeability in growth, invasivity and response to drugs is largely unknown due to the lack of characterisation techniques. We aim at deciphering the link between poroelasticity and mechanisms of drug action to obtain an integrated description of tumour biology.

It is necessary to recreate the mechanical complexity of tumours in in vitro models with a reductionist approach to test innovative therapies and implement new characterization techniques. Organoids are powerful in vitro models that are widely used in standardized preclinical studies to accelerate the translation of novel therapeutics to the clinic, but also as a tool to understand precisely tumour physics and biology. Formed from the controlled assembly of individual cells, they describe closely the complex tumour organisation, physiopathology and microenvironment. However these models challenge the standard microscopy techniques that use of fluorescent tags, which alter normal cell functions and eventually kill cells, hindering the study of drug kinetics over standard therapeutic time scales. Most importantly, they provide a contrast that does not reveal mechanical properties. For this, the impact of tumour mechanics on the response to drugs has been largely ignored, and novel imaging techniques that would incorporate mechanical properties as the contrast mechanism are sorely needed. Inspired by early theories of poroelasticity, we want to translate their experimental implementation in large scale geological systems to a tinier scale on organoids using optoacoustic techniques.

We will implement non-invasive mapping of the poroelasticity by detecting mechanical signals from the quasi-static range with opto-mechanical force sensors to the hypersonic range using light-scattering technologies. The analysis of the mechanics observed at contrasted time scales will allow probing elasticity and resistance to fluid flow. The poroelastic properties of organoids have never been studied, and the application of opto-acoustic techniques to life science is only starting to emerge. We therefore need to do the spadework for deciphering the link between poroelastic parameters and the structure of the organoid. We will compare the opto-acoustic measurements on organoids of increasing complexity in terms of composition and resistance to drug action to identify the key features of organoids. On these models, we will evaluate the impact of clinically relevant drug therapies using poroelasticity as a quantitative indicator, thereby optimizing dosimetry and exposure time to the treatment. The knowledge generated by our project will improve the predictability of in vitro models, and open new mechano-sensitive therapeutic routes. Furthermore, our results will define new mechanical indicators complementing histological data. The technologies we use hold great potential for in vivo translation and should provide new tools to guide clinicians in personalizing a therapy.

This work is supported by the Agence Nationale de la Recherche (ANR, grant no. ANR-17-CE11-0010-01) and  the Région Auvergne Rhône-Alpes (SCUSI no. 1700991901)

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Contact mechanics

Photoacoustic nano-indentation

Mapping metallic contacts with photo-excited electrons

Contacts between micro-spheres

Interfacial waves

Related publications:

       

  • T. Dehoux, O. B. Wright, R. Li Voti and V. E. Gusev, "Nanoscale mechanical contacts probed with ultrashort acoustic and thermal waves", Phys. Rev. B 80, 235409 (2009).

  • T. Dehoux, T. A. Kelf, M. Tomoda, O. Matsuda, O. B.Wright, K. Ueno, Y. Nishijima, S. Juodkazis, H. Misawa, V. Tournat and V. E. Gusev, "Vibrations of microspheres probed with ultrashort optical pulses", Opt. Lett. 34, 3740 (2009).

  • T. Valier-Brasier, T. Dehoux and B. Audoin, "Scaled behavior of interface waves at an imperfect solid- solid interface", J. Appl. Phys. 112, 024904 (2012).

  • M. Tomoda, T. Dehoux, Y. Iwasaki, O. Matsuda, V. E. Gusev, and O. B. Wright, "Nanoscale mechanical contacts mapped by ultrashort time-scale electron transport", Sci. Rep. 4, 4790 (2014).

  • Cell mechanics and tribology

    Cell rheology: analogy with fibrous materials

    Cell tribology probed by GHz acoustic waves

    Related publications:

                   

  • T. Dehoux, N. Tsapis and B. Audoin, "Relaxation dynamics in single polymer microcapsules probed with laser-generated GHz acoustic waves", Soft Matter 8, 2586 (2012).

  • M. Abi Ghanem, T. Dehoux, O. F. Zouani, A. Gadalla, M.-C. Durrieu, and B. Audoin, "Remote opto- acoustic probing of single-cell adhesion on metallic surfaces", J. Biophotonics 7, 453 (2014).

  • O. F. Zouani, T. Dehoux, M.-C. Durrieu, and B. Audoin, "Universality of the network-dynamics of the cell nucleus at high frequencies", Soft Matter 10, 8737 (2014).

  • A. Gadalla, T. Dehoux, and B. Audoin, "Transverse mechanical properties of cell walls of single living plant cells probed by laser-generated acoustic waves", Planta 239, 1129 (2014).

  • T. Dehoux, M. Abi Ghanem, O. F. Zouani, J.-M Rampnoux, Y. Guillet, S. Dilhaire, M.- C. Durrieu, and B. Audoin, "All-optical broadband ultrasonography of single cells", Sci. Rep. 5, 8650 (2015).

  • Single cell thermography

    Techniques that can probe thermal properties of cells are used in many applications ranging from cryogenic preservation to hyperthermia therapy, and provide powerful tools to investigate diseased conditions. The structural complexity of cells however requires innovative modalities operating at a subcell scale. We developed a label-free, non-ionizing technique based on a thermoelastic lens. With this device we captured images of single cells with a ~2 µm resolution based on thermal properties as the contrast mechanism. To investigate the thermorheological behaviour of cells, we present simultaneous acoustic imaging using an inverted opto-acoustic microscope. Acoustic impedances extracted from the acoustic images support the effusivity obtained from the thermal images. This technique should provide diagnostic tools at the single cell scale.

    Figure 1: On the left, a classical phase contrast image of a cell obtained via a standard microscope. On the right, a thermal image of the same cell recorded with the team’s thermal imaging device.


    Related publications:

                 

  • R. Legrand, M. Abi Ghanem, L. Plawinski, M.-C. Durrieu, B. Audoin, and T. Dehoux, "Thermal microscopy of single biological cells", Appl. Phys. Lett. 107, 263703 (2015).