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Rôle de la tyrosine kinase SYK dans la régulation du processus métastatique du mélanome

Abstract : The progression of tumors to metastatic disease involves the loss of metastatic suppressor functions, as it is the case in melanoma. Thus, aberrant cell migration is a key feature of melanoma progression, and is required for metastasis. SYK (Spleen tyrosine kinase) is a cytoplasmic tyrosine kinase that has been implicated in tumor suppression of breast cancer and melanoma. In skin cells, SYK is found expressed in melanocytes but SYK is frequently downregulated in melanoma by epigenetic silencing. We showed previously that its loss has been associated with senescence escape. Whether it also regulates tumor cell migration and subsequent metastasis remains poorly understood. In this work we used gain- and loss-of-function approaches to analyze SYK’s effects on metastatic abilities of human and murine melanoma cells. Respectively, the reexpression or knockdown of SYK results in decreased or increased migration, invasion and metastasis of melanoma cells. Notably, SYK knockdown cells displayed a mesenchymal-like phenotype with upregulation of mesenchymal markers. Our study unveils a novel role for SYK in suppressing integrin-mediated adhesion, both a points of traction and a signaling platform during cell migration, and outlines the importance of SYK inactivation in acquisition of a metastatic phenotype. To clarify the role of SYK in melanoma formation and progression, we have generated a conditional Syk KO mouse model in melanoma based on melanocyte-specific Pten loss and BrafV600E activating mutation. Preliminary results suggest that Syk loss does not accelerate Pten/Braf-driven melanoma formation but leads to deep invasion of Braf/Pten tumor cells into the dermis.
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Submitted on : Thursday, January 17, 2019 - 11:22:14 AM
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  • HAL Id : tel-01984709, version 1

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Emilien Garcia. Rôle de la tyrosine kinase SYK dans la régulation du processus métastatique du mélanome. Biologie moléculaire. Université Côte d'Azur, 2016. Français. ⟨NNT : 2016AZUR4154⟩. ⟨tel-01984709⟩

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