Les Spreading Initiations Centers et la traduction locale régulent l'adhésion et l'étalement des cellules mésenchymateuses

Authors: Bergeman, Jonathan
Advisor: Huot, Marc-Étienne
Abstract: In Canada, one person out of two will be diagnosed with cancer and one out of four will die of it, making cancer the leading cause of death (Statistiques canadiennes sur le cancer 2017. Toronto, ON: Société canadienne du cancer, 2017). This is mainly caused by metastasis formation, which is associated to more than 90% of the death related to cancer. While majority of cancers mostly originates from epithelial tissues, pre-metastatic cancerous cells can only leave the primary tumor after undergoing the epithelial mesenchymal transition (EMT). This transition allows cancerous cell lines to increase their ability to migrate through the highly structured stroma, invade the blood stream in order to disseminate in distant tissues. Increasing studies have shown causality in between RNA binding protein (RBP) and tumor progression. Our discoveries strengthen this hypothesis, as our work on Spreading initiation center (SIC), a transient structure during early adhesion, showed that RBPs regulation translation regulates these structure during mesenchymal cells adhesion and spreading. We found that SICs formation is controlled by RhoA activation and its inhibition will affect their formation and adhesion consolidation of mesenchymal cells. This consolidation is done with recruitment and enrichment of specific RBPs, mRNA and a high level of local translation in SICs. We also showed translational reprograming events during early adhesion, allowing us to find adhesion-regulated translation of specific mRNAs known to be implicated in cellular adhesion. Using our specifically engineered methods based on puromycin incorporation capacities, we identified neosynthesized proteins during early adhesion, showing a distinct translational activity. This also led us to show a specific enrichment of the mRNA coding for the newly synthetized proteins, through 3’UTR, within SICs. Finally, we showed that translation inhibition decreased the adhesion ability of mesenchymal cells and highly metastatic cancerous cells that undergo EMT, while not affecting epithelial cells or non-metastatic ones. Taken together, we conclude that SIC-regulated mechanism regulate mesenchymal cell adhesion through their ability to translate specific RNA, and that SICs can act as an adhesion checkpoint for metastatic cells, thus modulating their ability to disseminate and form metastases.
Document Type: Thèse de doctorat
Issue Date: 2019
Open Access Date: 18 March 2019
Permalink: http://hdl.handle.net/20.500.11794/34034
Grantor: Université Laval
Collection:Thèses et mémoires

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