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.
Pancreatic ductal adenocarcinoma (PDAC) remains a major health problem because it is among the most lethal malignant disease. The prognosis for this disease is poor despite diagnostic progress and new therapeutic and chemotherapeutic regimens. Early diagnosis of pancreatic cancer is difficult because of the lack of obvious symptoms and signs as well as of early markers. Efforts to develop therapies that counteract the oncogenic effects of Kras have been largely unsuccessful and cancers driven by mutant Kras remain among the most refractory to available treatments. Knowing the molecular mechanisms that subtend the cancer development and sustain the drug resistance is urgently needed. Therefore, we propose to unravel the intricate signalling network that underlies the development of pancreatic ductal adenocarcinoma (PDAC), where the presence of a Kras mutation is frequently associated with a worse prognosis. Of note, we have recently identified a novel role for the intracellular domain of the Notch-ligand Jagged1 (Jag1-ICD), which behaves as an oncogenic driver when it is constitutively cleaved by Kras/ERK-signalling dependent, with important effects on development, cancer spread and drug resistance in solid tumours, such as in colorectal cancer. We believe that Jag1-ICD-triggered signalling may sustain also PDAC growth and aggressiveness, where Kras is a dominant mutation and Jag1-ICD is strongly expressed. Notably, several crucial aspects about PDAC aggressiveness remain still unclear and little is known about the role of Jagged1 in tumour biology. Interestingly, the reverse signalling triggered by Jag1-ICD is an unexplored pathway inside solid tumors and this represents the novelty of the project, which could allow us to achieve new crucial goals in the knowledge about cancers. To this aim, we will focus our attention to characterize better the impact of Jagged1 signalling pathway inside PDAC tumor cells, and 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.
It has been quite accepted the concept that the tumoral cells ability to escape from chemotherapeutic treatments is tightly correlated with a deregulated network of major signalling pathways concurrently impinging on several targets. Therefore, we speculate that Jagged1 may represent a keystone in managing drug resistance acquisition in PDAC. In fact, we believe that Jagged1 may be a potential target to generate new therapeutic approaches Jagged1-based, in order to overcome drug resistance and ameliorate the PDAC cancer-affected patients life. Interestingly, the data collected by this research may help us to identify a new prognostic and predictive factor in PDAC cancer, or a molecular biomarker for disease staging, which are still missing. The final goal will be to value the repositioning strategy of old drugs to obtain an improvement of the current therapeutic approaches for PDAC tumours. This research will lead to results that could be soon transferred in the clinical field of human oncology.