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• W2947012783 abstract "Skin has long been a benchmark for early steps of cancer development. Many cancer driver mutations are already found in apparently normal epidermal tissue, pointing to the importance of concomitant dermal changes. Possible genomic alterations in underlying dermal cells remain to be investigated. We find that DNA damage, telomere shortening and chromosome fusions occur at early steps of cancer associated fibroblast (CAF) activation due to loss of CSL (RBP-JK), a DNA binding protein with both NOTCH-related and unrelated functions. Separately from its role in transcription, CSL is an essential component of a telomere protective complex, which binds directly to the UPF1, KU70, and KU80 proteins and is required for their association to chromosome ends. In clinically-derived CAFs, in which CSL is down- modulated, persistent genomic instability is associated with N0TCH1 gene amplification and increased expression, which blocks the DNA damage response (DDR) and DDR-mediated growth arrest. The findings are of translational significance as, in an orthotopic model of skin Squamous Cell Carcinoma, genetic or pharmacological inhibition of NOTCH activity suppresses CAF / cancer cell proliferation and expansion.--La peau a ete longtemps une reference pour les premieres etapes du developpement du cancer. De nombreuses mutations du cancer sont observes deja dans les tissus epidermiques apparemment normaux, soulignant l'importance des modifications cutanees concomitantes. Les possibles alterations genomiques des cellules dermiques sous-jacentes restent a etudier. Nous trouvons que les lesions de l'ADN, le raccourcissement des telomeres et les fusions chromosomiques surviennent aux premiers stades de l'activation des fibroblastes associes au cancer (CAF) en raison de la perte de CSL (RBP-JK), une proteine liant l'ADN avec des fonctions liees a NOTCH et independantes. Separement de son role dans la transcription, le CSL est un composant essentiel d'un complexe protecteur des telomeres, qui se lie directement aux proteines UPF1, KU70 et KU80 et est necessaire a leur association aux extremites chromosomiques. Dans les CAF derivees des patients, dans lesquelles la CSL est modulee vers le bas, l'instabilite genomique persistante est associee a l'amplification du gene NOTCH1 et a une expression accrue, qui bloque la reponse aux dommages a l'ADN (DDR) et l'arret de la croissance causee par DDR. Les decouvertes ont une signification translationnelle puisque l'inhibition genetique ou pharmacologique de l'activite NOTCH dans un modele orthotopique de carcinome epidermoide cutane supprime la proliferation et l'expansion des CAF e des cellules cancereuses." @default.
• W2947012783 created "2019-06-07" @default.
• W2947012783 creator A5049359903 @default.
• W2947012783 date "2018-01-01" @default.
• W2947012783 modified "2023-09-27" @default.
• W2947012783 title "CSL and NOTCH1 determine genomic stability and expansion of Cancer Associated Fibroblasts in human skin" @default.
• W2947012783 hasPublicationYear "2018" @default.
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