The Notch Pathway Promotes Osteosarcoma Progression through Activation of Ephrin Reverse Signaling
Menée à l'aide d'échantillons tumoraux prélevés sur 12 patients atteints d'un ostéosarcome et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel la voie de signalisation Notch favorise la progression de la tumeur via l'activation de la voie de signalisation inverse des éphrines
Despite significant advancements in the diagnosis and treatment of osteosarcoma, the molecular mechanisms underpinning disease progression remain unclear. This work presents strong clinical and experimental evidence demonstrating that Notch signaling contributes to osteosarcoma progression. First, using a cohort of 12 patients, Notch genes were up-regulated in tumors compared to adjacent normal tissue, and high tumour expression of Notch1 intercellular domain (NICD1) and the Notch target gene Hes1 correlated with poor chemotherapy response. Data mining of publically available datasets confirmed that expression of Notch pathway genes is related to poor prognosis in osteosarcoma. Based on in vitro analysis, Notch signaling promoted osteosarcoma proliferation, enhanced chemoresistance, facilitated both migration and invasion, and up-regulated stem-cell like characteristics. Xenograft models demonstrated that Notch signaling promotes primary tumor growth and pulmonary metastasis, and Notch inhibition is effective in reducing tumour size and preventing metastasis. Mechanistically, activated Notch signaling induces the expression of ephrinB1 and enhances the tumor-promoting ephrin reverse signaling. Overall, these findings provide functional evidence for Notch pathway genes as candidate biomarkers to predict prognosis in osteosarcoma patients, and suggest a mechanistic rationale for the use of Notch inhibitors to treat osteosarcoma. Implications: The study provides preclinical evidence for Notch pathway as a molecular marker to predict osteosarcoma prognosis and as a therapeutic target against osteosarcoma. In addition, we identified a novel mechanism that ephrin reverse signaling acts as a key mediator of Notch pathway.