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Identification de SHISA3 comme gène médiateur de la transition épithélio-mésenchymateuse dans le cancer de la prostate résistant au docetaxel

Abstract : Prostate cancer is the most common cancer in men and the third leading cause of cancer mortality in France. Since 2004, docetaxel is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC). However, nearly half of treated patients develop resistance to chemotherapy. The aim of my thesis is to identify molecular predictors to select patients who will respond to docetaxel chemotherapy. My second goal is to identify new therapeutic targets to overcome this resistance, by studying the molecular mechanisms involved in the development of resistance.To this purpose, genes and microRNAs expression profiles were established in several cellular models of docetaxel-resistant prostate cancer. The integration of these high-throughput data suggested that the epithelial-mesenchymal transition (EMT) was involved in the mechanism of docetaxel resistance. Deciphering the EMT mechanism observed in our cellular models allowed the identification of SHISA3 as a new regulator of this process. SHISA3 is highly under-expressed in docetaxel resistant cells which present a mesenchymal phenotype. Interestingly, SHISA3 is also down-regulated in a large variety of human tumors. The inhibition of SHISA3 in sensitive cells induced a complete EMT, characterized by loss of cellular junctions, expression of mesenchymal transcription factors, and increased migratory capacity. The study of its mechanism of action allowed us to highlight the interaction of SHISA3 with TGFβRII. We showed in docetaxel-resistant cells that pharmacological inhibition of the TGFβ signalling pathway induces sensitization to docetaxel, demonstrating the importance of the regulation of this pathway in the resistance to chemotherapy.In parallel, we developed a docetaxel-resistant prostate cancer model in mice. The establishment of this model is critical for the preclinical validation of new targeted therapies. Tumors obtained from this new model are characterized by the under-expression of SHISA3 and the expression of EMT markers. This model will allow the validation of the therapeutic potential of co-treatment with docetaxel and TGFβ signalling pathway inhibitors in vivo. Interestingly, we observed that SHISA3 expression is correlated with response to docetaxel treatment in vivo. These results suggest that SHISA3 could be a biomarker of response to docetaxel chemotherapy.
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https://tel.archives-ouvertes.fr/tel-01221968
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Submitted on : Thursday, October 29, 2015 - 1:01:21 AM
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Nicolas Martin. Identification de SHISA3 comme gène médiateur de la transition épithélio-mésenchymateuse dans le cancer de la prostate résistant au docetaxel. Cancer. Université Paris Sud - Paris XI, 2014. Français. ⟨NNT : 2014PA11T057⟩. ⟨tel-01221968⟩

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