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Règulation du développement de la crête neurale embryonnaire et de la progression du mélanome adulte par une fonction non conventionnelle de PFKFB4

Abstract : Control of cell migration is highly conserved between embryo and metastasis formation from primary tumors. The neural crest (NC) is a multipotent cell population defined by its migratory properties, giving rise to multiple derivatives as bones and cartilages of the face or melanocytes which are pigmented cells of the skin. Cellular and molecular properties of NC make of it a very good physiological model helping to understand the development of metastasis. Monsoro-Burq team identified a new regulator of NC in vivo, known to regulates glycolysis, called PFKFB4. The team demonstrated that PFKFB4 is essential for NC induction, in a glycolysis independent manner, via PI3K/AKT signaling (Pegoraro et al., 2015). The aim of this thesis is to establish if this new link between PFKFB4 and AKT activation is important during NC migration and in an invasive cancer context, as well as defining what are the underlying molecular mechanisms. First, we have shown that PFKFB4 is playing a double role, both on glycolysis and PI3K/AKT signaling to control NC cell migration (Figueiredo et al., 2017). Secondly, we chose to study this regulation in human melanoma cell line, a model of neural crest derived cancer, where PFKFB4 is overexpressed. We have shown that PFKFB4 control cell migration independently of its role in glycolysis, as during NC development. In melanoma and in NC, we found that PFKFB4 act indirectly on AKT. We looked for a partner of PFKFB4 with mass spectrometry and identified ICMT, a regulator of RAS subcellular localization. Finaly, we explored the importance of this interaction in AKT activation and melanoma cell migration (Sittewelle et al., 2020). This thesis work allowed to explore the molecular detail by which PFKFB4, a cell metabolism regulator, also control the response of cells to signals from their environment and their migration, by a non-canonical mechanism. Our results allow us to describe a new fundamental link in the coordination of cell migration in the physiological context of embryonic cell migration and pathological context of metastasis.
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Submitted on : Sunday, October 2, 2022 - 1:02:39 AM
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  • HAL Id : tel-03793793, version 1

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Méghane Sittewelle. Règulation du développement de la crête neurale embryonnaire et de la progression du mélanome adulte par une fonction non conventionnelle de PFKFB4. Embryologie et organogenèse. Université Paris-Saclay, 2020. Français. ⟨NNT : 2020UPASL007⟩. ⟨tel-03793793⟩

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