Rôle de la nanobiomécanique dans la formation de métastases cérébrales et la sclérose latérale amyotrophique

Abstract : Nano-biomechanics is an emerging field of science that opened a new horizon in scientific research by generating significant contribution in the study of human diseases. In this work, atomic force microscopy-based nanomechanical methods were directly applied in order to elucidate important questions related to brain metastasis formation and amyotrophic lateral sclerosis (ALS). Better understanding of the underlying pathogenic processes of these life-threatening diseases is fundamental for the advancement of early diagnostics and improved therapeutics.A malignant tumor cell, in order to spread and form metastasis, has to vary and continuously adapt its adhesive and elastic properties. Here, we combined force mapping with single cell force spectroscopy (SCFS) in order to gain direct insight into the surface “screening” process of tumor cells during their extravasation into the brain parenchyma. Intercellular adhesive forces and works, as well as elastic properties were spatially mapped showing that adhesive properties are only slightly dependent on elastic characteristics, and highlighting the importance of long range tether-like linkages for successful adhesions.In order to examine how the metastatic potential relates to tumor cell’s autonomous and inter-cellular nanomechanical properties, comparative SCFS measurements were performed between three melanoma cell types (WM35, A2058 and A375), showing altered invasive characteristics, and blood vessel lining endothelials. Our results indicate low relative elasticity, high maximal adhesion and high number of individual linkages, as the key properties of highly metastatic melanoma cells. This enables us to suggest the following ordering of tumor cells from lower to higher metastatic potential: WM35, A2058 and A375.The pathogenesis of ALS is multifactorial, being characterized by the presence of inflammatory processes as well. In our results significant differences have been observed, by comparing the adhesion of CD8+ cytotoxic T cells isolated from wild-type as well as SOD1G93A mutant mice against wild-type motor neurons. Mutant mice derived T cells show enhanced adhesion strength, compared to the healthy mice derived ones. Moreover, we observe a significant reduction of T cell - motoneuron interactions after blocking the specific recognition bindings between pMHC-I and TCR. These results corroborate the contribution of cytotoxic T cells in the development of ALS, as an active player in neurodegeneration.Investigating primary myoblasts allow deciphering molecular processes involved in muscle development, aging and repair. Therefore, in our study high resolution nanomechanical mapping was performed on single elongated myoblasts and multinuclear myotubes, isolated from an ALS mouse model, to reveal elasticity features during early differentiation stage into myotubes. We have found that projections of the elongated myoblasts show significantly increased elastic modulus values compared to their cell body. Regarding myotubes, differences have been observed between the elasticity of a thin and thick population of wild-type myotubes, indicating the different maturity of the two populations. However, in SOD1 mutant, the observed increase in the elastic modulus of the thin population suggests an enhanced autonomous hardening of ALS derived myotubes.In summary, our cellular-level mechanical studies deciphered various aspects of two different life-threatening pathologies resulting in novel discoveries about their fundamental processes. This work highlights the high impact and the important role of AFM-based nanomechanical methods in providing valuable knowledge about disease pathophysiology, development, diagnostics and progression that could contribute to the evolvement of future therapies.
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Béla Varga. Rôle de la nanobiomécanique dans la formation de métastases cérébrales et la sclérose latérale amyotrophique. Biophysique. Université Montpellier; University of Szeged (Hongrie), 2018. Français. ⟨NNT : 2018MONTS085⟩. ⟨tel-02276752⟩

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