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, Poster des échappements thérapeutiques, dus à la résistance des cellules cancéreuses. Ces données soulignent donc la nécessité d'identifier de nouveaux biomarqueurs de résistance des cellules de CCR au 5-FU. Les travaux réalisés au cours de cette thèse ont porté sur l'étude de la sortiline, une protéine « multi-tâches » appartenant à la famille des récepteurs à domaine VPS10 avec sorLA et sorCS1-3, Limoges : Communication Orale ? Journée scientifique du G4F (Groupe de Fractionnement Flux Force Français) (2016) -Nantes : Communication orale + Poster ? Journée GEIST, 2015.

). La-sortiline-(et-non-sorla, In vivo et in vitro, au sein des tumeurs et des cellules de CCR (lignées cellulaires et cultures primaires) résistantes au 5-FU, seule la sortiline apparait surexprimée au niveau transcriptomique et protéique. Ces données indiquent que la sortiline constitue également un biomarqueur de résistance au 5-FU, quels que soient les grades, stades et statuts mutationnels. Cette surexpression de la sortiline est majoritairement localisée au sein de l'appareil de Golgi des cellules résistantes et semble être régulée transcriptionnellement via une down-régulation d'ATF-3. L'inhibition génétique (shRNA) ou pharmacologique (CADA) de la sortiline potentialise les effets cytotoxiques du 5-FU. Au contraire, sa surexpression protège les cellules. La sortiline semble donc être également impliquée dans la résistance des cellules de CCR au 5-FU ; l'expression de sorLA ne variant pas après son inhbition ou sa surexpression. Ces résultats suggèrent que la sortiline pourrait constituer un biomarqueur d'agressivité

, Even when 5-FU is used as the first-line molecule, responsiveness is only 20-30%, and drug resistance contributes to both poor patient prognosis and relapses, emphasizing the need to identify biomarkers involved in this process. In this study, we focused on sortilin, a multifunctional protein among VPS10 domain-related receptors with sorLA and sorCS1-3, that acts as a receptor and co-receptor as well as a regulator of intra-and extracellular protein sorting and trafficking. We obtained evidence that sortilin, but not sorLA, is a biomarker of CRC aggressiveness associated with poor clinical outcomes. In vivo and in vitro, in both 5-FU-resistant CRC cell lines and primary cultures, only sortilin was overexpressed at both protein and mRNA levels, indicating that it could serve as a biomarker of 5-FU resistance regardless of tumor grade and mutational status. Sortilin overexpression is especially localized in Golgi apparatus of 5-FU resistant cells and seems to be transcriptionally regulated through ATF-3 downregulation. Genetic (shRNA) and pharmacological (CADA) inhibition of sortilin potentiated 5-FU-induced cytotoxicity. On the contrary, sortilin overexpression protected CRC cells from 5-FU., thus implying that sortilin is also actively involved in 5-FU resistance. Moreover, sorLA expression is unchanged upon neither sortilin inhibition nor transient overexpression, Mots-clés : 5-fluorouracil, biomarqueur, cancer colorectal, grade tumoral, résistance, sortiline Abstract Worldwide, colorectal cancer (CRC) is the second leading cause of cancer-related deaths