Notch3 Pathway Alterations in Ovarian Cancer

Menée à partir de données issues du projet "The Cancer Genome Atlas", puis in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels des anomalies d'expression du gène Notch3 favorisent la progression d'un cancer de l'ovaire

Résumé en anglais

Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biological mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited OvCa growth and induced apoptosis. Importantly, we found that DNM-mediated endocytosis was required for selectively activating Jagged-1-mediated Notch3 signaling. Cleaved Notch3 expression was the critical determinant of response to Notch-targeted therapy. Collectively, these data identify previously unknown mechanisms underlying Notch3 signaling and identify new, biomarker-driven approaches for therapy.