Pancreatic ductal adenocarcinoma (PDAC) remains a major health problem because it is among the most lethal malignant disease. Early diagnosis of pancreatic cancer is difficult because of the lack of obvious symptoms and signs as well as of early markers for this highly aggressive disease. The oncogenic Kras mutation is the major event in pancreatic cancer; it confers permanent activation of the Kras protein, which acts as a molecular switch to activate various intracellular signalling pathways, as Erk/MAPK pathway, and nuclear transcription factors, leading to stimulation of cell proliferation, transformation and migration in PDAC cancer.  Interestingly, increased expression levels of Jagged1 are closely correlated with severe clinicopathological characteristics and poor prognosis in patients with pancreatic ductal adenocarcinoma. The commonly accepted scenario is based on the idea that the Jagged1 ligand can 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/γ-secretase complex, ultimately resulting in the release of a nuclear-targeted intracellular domain (Jag1-ICD), able to trigger an its own “reverse” signalling in cancer cells. Recently, we have demonstrated the existence of a reverse signalling pathway Jag1-ICD-dependent, which may activate an intricate network of signals insight the tumor cells, favouring cancer development, progression and chemoresistance. For the first time, we have pointed out a novel role for Jag1-ICD in tumour biology that may go beyond its effect on canonical Notch activation. Moreover, we have demonstrated 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 Jagged1 in a novel Jag1-ICD oncoprotein. Therefore, the aim of this proposal is to investigate the role of the Kras/Erk/ADAM17/Jagged1 signalling axis in PDAC tumorigenesis, following a non-canonical mechanism, based on Jagged1 reverse signalling. This study may open new undiscovered scenarios and give the opportunity to face new important aspects, useful to better understand its role in PDAC progression/invasion and therapy resistance.