Background: Pancreatic cancer have a multi step progression model with successive mutations like activation of KRAS and inactivation of SMAD 4. Various studies demonstrated that loss of SMAD 4 cooperate with an activating KRAS mutation to promote progression, leading to dysregulation of TGFb pathway. This plays a pivotal role in the formation of desmoplastic reaction by the activation of stellate cells. Stromal cells synthesize and secrete multiple proteins like SPARC which has been associated with worst prognosis. Early data have suggested that the identification of cancer stem cells in primary tumors is associated with shorter OS, resistance to therapy and metastatic potential. Emerging evidence suggest that the activation of the NOTCH 1 pathway is associated with molecular characteristics of stem cells. The aim of our study is to investigate the relationship and the potential prognostic role of these biomarkers. Methods: In 110 histological samples of pancreatic ductal adenocarcinoma were performed immunohistochemical evaluations of KRAS, and molecular biology assessment of NOTCH 1 CD133, OCT3/4, SMAD 4, SPARC. Results: Preliminary analysis showed lower rate of KRAS mutations (54%) and higher expression of NOTCH 1 in KRAS WT patients (57% vs 41%). Different expression of OCT3/4 and CD133 was found according to NOTCH1 expression. In patients with NOTCH1 overexpression, OCT3/4 is found overexpressed (59% vs 45%). Instead in patients with lower NOTCH1 expression CD133 is overexpressed (59% vs 42%). Furthermore KRAS WT compared to MT patients showed higher expression of SMAD4 (66% vs 37%) and lower expression of SPARC (44% vs 59%). Conclusions: Our data indicate that KRAS status can differentiate two prognostic categories of pancreatic tumors: one (KRAS MT) probably more aggressive and characterized by early metastatization, associated to desmoplastic reaction and stemness (higher SPARC and CD133), the other (KRAS WT) with a more favourable behavior, correlated with a prevalent local invasiveness, with lower desmoplasia and stemness profile (lower SPARC and higher OCT3/4). These data suggest that the latter tumors are good candidates to radiotherapy as a part of combinated treatment.