Pancreatic ductal adenocarcinoma (PDAC) remains a major health problem because it is among the most lethal malignant disease. The oncogenic Kras mutation is the major event in pancreatic cancer and it is frequently associated with a worse prognosis; it confers permanent activation of the Kras protein, which acts as a molecular switch, able to activate Erk/MAPK pathway leading to pancreatic cell transformation. Interestingly, increased expression levels of Jagged1 are closely correlated with severe clinicopathological characteristics and poor prognosis in patients with PDAC. The commonly accepted scenario is based on the idea that the Jagged1 ligand is able to contribute to tumorigenesis, by activating canonical Notch signalling. Notably, Jagged1 may be processed in a fashion similar to Notch by sequential proteolytic cleavages that involve two distinct enzymes: ADAM-17/TACE and PS/¿-secretase complex, ultimately resulting in the release of a nuclear-targeted intracellular domain (Jag1-ICD), able to trigger an its own ¿reverse¿ signalling. Initial in colorectal cancer, we pointed out a novel oncogenic role for Jag1-ICD in tumour biology that may go beyond its effect on canonical Notch activation, favouring cancer development, progression and chemoresistance. We observed that Jag1-ICD ¿reverse¿ pathway is constitutively activated when Kras/Erk/ADAM17 signalling is switched on, demonstrating that Jagged1 is a novel proteolytic target of Kras signalling pathway, able to transform the proto-oncogene Jagged1FL in a Jag1-ICD oncogene. Since, mutations that activate KRAS are the most common oncogenic events in PDAC cancer (90%), our hypothesis is that Jag1-ICD may be an oncogenic driver, activated by Kras/Erk axis, able to play a direct role in sustaining PDAC cancerogenesis, relapse and drug resistance. The aim of this project is to investigate the role of the Kras/Erk/ADAM17/Jagged1 signalling axis in PDAC cancerogenesis, following a non-canonical mechanism.
