Final Report Summary - NOTCH PROTEOLYSIS (Targeting the Notch Protease Interface)
Notch signaling is a cell-cell communication system important for establishment and maintenance of embryonic and adult tissues. There are four Notch receptors with distinct and overlapping functions that are frequently implicated in cancer development and treatment resistance. The aim of this project was to identify key steps in the Notch signal transduction in normal versus cancer cells, and to establish models to address the importance of Notch signaling in cancer development and treatment resistance. Here we identified ADAM10 as the crucial enzyme involved in ligand dependent NOTCH1, 2 and 3 signal transduction in normal cells. In ligand independent signaling such as observed in cancer cells other proteases can cleave Notch receptors as well. Using an unbiased screening approach we have identified many genes that are important in the Notch activation in the absence of Adam10 which are currently being validated. Furthermore we have shown that activation of the Notch signaling pathway in human lung cancer is associated with a poor outcome and response to radiation therapy. One of the causes for is that Notch signaling promotes the survival of treatment-resistant cancer cells. Research is now focused on further identifying these mechanisms and exploiting this knowledge for enhancing therapeutic interventions.