Our research focuses on biological problems that we rephrase as physics questions to better understand how living matter works. This led us to study how out-of-equilibrium properties can act as determinants of the behaviour of cells and multicellular assemblies. We focused on the steady-state dynamics of epithelial cytoskeleton and on a relaxation instability required for cell motility. We now study the social aspects of phenotype plasticity and stability, to understand the nucleation of tumor using optogenetics. We also develop optical instruments for our research needs and for diagnostic applications.
Using the human pathogenic parasite Entameoba histolytica, we studied bleb-based motility in vivo and in vitro, and found that blebs are steadily produced by a relaxation instability of the intracellular pressure. This regime is part of a dynamic phase diagram that depends on 3 parameters: the strength of the membrane-cytoskeleton interactions, the rate of actin turnover, and acto-myosin contractility (fig.1).
Because epithelia are mechanically active, we assumed that their stability required an active process to mutually adjust contractile intercellular forces at intercellular junctions. We found that E-cadherin dynamics is rate-limited by endocytosis and its turnover could provide the pace at which contractile forces are ajusted. The rate of endocytosis is mechanosensitive and matches across single junctions. Various cell biology and physical method were used or developed for these investigations, including two-photon two-color FRAP and non-linear optical polymerization of resins, hydrogels, or proteins (figure 2).
Our results indicated that individual junctions behave autonomously at short times, and this opens a difficulty: since stability is not a single-cell property but pertains to two cells at least, how will a junction respond if instability is induced only one of its two partner cells? Because epithelial cells obviously interact in many ways, the response of a cell to a given genetic or biochemical perturbation within an epithelium will most likely depend on whether the perturbation has been brought to that cell only or a few neighbours (heterogeneous perturbation), or to all cells (homogeneous). This trivial idea that social interactions should modulate cellular responses, and that homogeneous vs. homogeneous perturbations should elicit different responses led us to a new research programme. First, we investigate how disorder nucleates within an epithelium, upon the heterogeneous genetic induction of the epithelial-to-mesenchymal transition -EMT. To this end, we put the EMT inducer gene snail under optical control to distribute its activation in individual cells with arbitrary patterns in time and space (3D). This should reveal the social and geometric rules underlying the stability of the epithelial phenotype, which oppose the EMT. Second, using primary human breast carcinoma cell exhibiting a spontaneous and self-regenerating phenotypic diversity, we seek to quantify to which extend cell-fate decisions and phenotypic plasticity are cell-autonomous mechanisms, or results from mutual interactions. Interdependence is necessary to create normal tissues, and its rules are probably altered or lost in tumors. In the same spirit, we study in parallele the behavior of epithelia, in the context of the renal tube, to delineate the mechanical and geometric determinants of tubulogenesis and pathological cystogenesis.
We also develop a novel imaging method, based on laser-induced thermal radiation pulses and a unique single-photon sensitive camera is being prototyped in the mid-infrared band, for ultrasensitive thermal pulse imaging of pigmented circulating tumor cells. In collaboration with Curie oncologists, it will be used for counting circulating melanoma cells for early detection of the metastatic disease.