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Destruction du microenvironnement tumoral par application de forces mécaniques exercées par des nanoparticules magnétiques

Abstract : Efficiency of anti-cancer treatments is limited by development of resistance to treatments, which has long been considered to depend solely on the genotype of cancer cells. However, these past few years, researchers proved that cancer progression and resistance are not only determined by the inherent characteristics of cancer cells, but also by their interactions with tumor microenvironment. Among other components of the tumor microenvironment, cancer-associated fibroblasts (CAFs) promote tumor growth and cancer cell resistance to treatments. CAFs modify the components and properties of tumor microenvironment (blood vessels, extracellular matrix or tumor immunity) and interact with cancer cells; those actions take a great part in the loss of treatment efficacy. Thus, as CAFs seem to be key players in cancer cell resistance to treatment, their eradication is an interesting strategy to inhibit cancer progression. While magnetic nanoparticles (MNPs) under a high frequency magnetic field produce heat, they generate a mechanical torque in response to low frequency rotating magnetic fields (RMF) Here, we chose this last property to elaborate a nano-therapeutic strategy directed against CAFs. The principle of this strategy is to target CAFs using vectorised MNPs and then apply a RMF that generates enough mechanical stress to induce cell death. The first objective was to target pancreatic CAFs that express the type 2 cholecystokinin receptor (CCK2R). For this, we synthesized gastrin-decorated MNPs (MNP@Gastrin). We showed that MNP@Gastrin bind to the CCK2R on the cell membrane of CAF-CCK2R, then internalize and accumulate in the lysosomes. Then, we tested different amplitudes and frequencies of RMF and demonstrated that RMF exposure induces the death of CAFs having accumulated MNP@Gastrin into their lysosomes. The optimal effect on cell death, namely the death of about 40% of CAFs, was obtained with 40mT and 1Hz RMF. Moreover, we investigated the cell death mechanism involved and we showed that cell death occurs through lysosomal damage. Lysosomes undergo membrane permeabilization, releasing their content, including cathepsin B which are involved in the observed cell death process. On top of that, the engaged cell death pathway seems to be caspase-1 dependent. Finally we used a magnetic setup under a confocal microscope in order to observe real-time cell reaction to RMF. We noticed cellular retraction, lysosomal movements towards the nucleus, and changes in cellular adhesion. This study establishes the proof-of-concept that targeted MNPs can disrupt tumor microenvironment through mechanical forces upon RMF exposure, and thus open new opportunities for cancer therapy.
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Sarah Lopez. Destruction du microenvironnement tumoral par application de forces mécaniques exercées par des nanoparticules magnétiques. Cancer. Université Paul Sabatier - Toulouse III, 2019. Français. ⟨NNT : 2019TOU30202⟩. ⟨tel-02619686⟩

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