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Le mélanome uvéal est un cancer fortement métastatique et à ce stade il est chimiorésistant et radiorésistant [14]. Le succès du traitement de la tumeur de l’oeil ne prévient pas l’apparition de métastases au foie des années plus tard; cela suggère que des microlésions hépatiques en dormance sont présentes au moment du diagnostic initial. Malgré la disponibilité d’excellents outils pronostiques pour déterminer le risque d’apparition de métastases, les traitements disponibles actuellement permettent seulement de ralentir brièvement la progression des métastases, mais il n’en existe pas de curatif. L’objectif général de mon projet de thèse est de caractériser des mécanismes moléculaires à potentiel thérapeutique dans la progression métastatique du mélanome uvéal qui pourraient être ciblés au sein d’une thérapie adjuvante chez les patients à haut risque de développer des métastases.

Mon premier objectif consistait à caractériser les effets de la répression du récepteur 2B de la sérotonine (HTR2B) dans les cellules cancéreuses métastatiques du mélanome uvéal. L’hypothèse que nous proposions était que la réexpression aberrante de HTR2B favorise la survie et la dissémination des cellules cancéreuses hors de l’œil. Ainsi, nous avons

caractérisé les effets pharmacologiques d’un inhibiteur de HTR2B dans trois lignées métastatiques par des essais cellulaires de prolifération, de migration et la détection du niveau de phosphorylation des kinases. Les résultats de cette étude sont présentés sous forme d’un manuscrit au Chapitre 2.

Mon deuxième objectif consistait à caractériser le profil d’hydroxyméthylation de l’ADN durant la progression du mélanome uvéal. Notre hypothèse était que la reprogrammation de l’hydroxyméthylation (5-hmC) du génome de ce cancer favorisait sa dédifférenciation et sa dissémination métastatique. Nous avons étudié le niveau de 5-hmC dans l’ADN de 6 six lignées cancéreuses dérivées de cas non métastatiques ou métastatiques et de mélanocytes choroïdiens par des techniques biochimiques et par HPLC/MS-MS. L’expression et la présence de mutations dans les enzymes déméthylantes IDHs ont été déterminées par séquençage de type Sanger, profilage génique et immunobuvardage Western. Les résultats de cette étude sont présentés sous forme d’un manuscrit au Chapitre 3.

Enfin, mon troisième objectif consistait à tester différents taux d’oxygène pour la culture in

vitro des lignées mélanocytaires. L’hypothèse que nous proposions était qu’un taux

d’oxygène physiologique (3% O2) favorisait l’expansion des mélanocytes oculaires en

réduisant le stress oxydatif associé à la culture à 21% O2. Ainsi, nous avons caractérisé le

niveau de différenciation, la prolifération et le transcriptome des mélanocytes choroïdiens par des essais cellulaires de prolifération, du profilage génique et des immunobuvardages Western, en comparaison avec les cellules cancéreuses du mélanome uvéal. Les résultats de cette étude sont présentés sous forme d’un manuscrit au Chapitre 4.

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