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Validation de la protéine Kinase D1 comme facteur pronostique et cible thérapeutique dans le cancer du sein triple négatif et analyse de son rôle dans le maintien du phénotype mésenchymateux dans le mélanome

Abstract : PKD1 is a serine-threonine kinase encoded by the PRKD1 gene. It belongs to the protein kinase D (PKD) family. The PKD family also includes PKD2 and PKD3 which share a high structural similarity with PKD1. Some studies suggest that PKD1 is involved in many oncogenic pathways such as MAPK, NF-κB, HDAC... Recent data from our group showed that PKD1 is more expressed in melanoma cell lines with mesenchymal phenotype compared to melanoma cell lines with epithelial phenotype. We also showed that PKD1 participates in the development and/or maintenance of the estrogen-independent phenotype in breast cancer, and that high PKD1 mRNA levels were associated with a worse outcome in tamoxifen-treated tumors. The objective of my thesis is to analyze the role of PKD1 in the maintenance of mesenchymal phenotype in melanoma and to determine whether PKD1 could be a prognostic factor and/or a therapeutical target for the treatment of breast cancer subpopulations. We analyzed molecular markers involved in mesenchymal and epithelial phenotype (cadherin, β-catenin …) and the functional characteristics of mesenchymal melanoma cells after PKD1 pharmacological inhibition. Results suggest that PKD1 inhibition induced a mesenchymal to epithelial like transition in these melanoma mesenchymal cell lines. In addition, the expression of PRKD1, PRKD2 and PRKD3 was analyzed by RT-qPCR in 527 breast cancers. We showed that higher PRKD1 mRNA levels were associated with a lower metastasis-free survival in the overall breast cancer population. PRKD1 prognostic value was even stronger in ERα- and in triple negative tumors. Then, we tested PKD1 inhibitors in collaboration with the AB Science pharmaceutical company. We assessed the anti-tumoral activity of PKD1 inhibitors in vitro in TNBC (triple negative breast cancer) cell lines and in vivo in a TNBC PDX (patient derivated xenograft) model. PKD1 pharmacological inhibition or depletion by siRNA reduced colony forming units in MDA-MB-436 TNBC cells. PKD1 pharmacological inhibition also reduced tumor growth in vivo in TNBC PDX model. Following those results, we analyzed PRKD1 expression in different multi-cancer cohorts. Our results showed that higher PRKD1 expression is found in melanoma and glioblastoma. In conclusion, results showed that PKD1 could participate in the maintenance of mesenchymal phenotype in melanoma. And that PKD1 could be an interesting therapeutic target in melanoma, breast cancer and glioblastoma.
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Caroline Spasojevic. Validation de la protéine Kinase D1 comme facteur pronostique et cible thérapeutique dans le cancer du sein triple négatif et analyse de son rôle dans le maintien du phénotype mésenchymateux dans le mélanome. Cancer. Université Paris-Saclay, 2017. Français. ⟨NNT : 2017SACLS404⟩. ⟨tel-01773208⟩

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