Research topics
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)
Related publications:
Financial support:
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).
