Pancreatic cancer is one of the most lethal human cancers with a five-year survival rate of less than 5%. Late presentation and a high level of resistance to chemotherapeutic drugs are among the major reasons for this dismal prognosis. The presence of the highest degree of desmoplasia among all solid tumours and the fact that chronic inflammatory pancreatic disease is associated with an increased risk for pancreatic cancer indicate, that the tumour microenvironment is of particular importance for carcinogenesis in the pancreas. The long-term objective of this proposal is to increase survival of pancreatic cancer patients by exploring the contribution of the tumour microenvironment to the failure of presently available oncological treatments. For this purpose the clinical observation will be reverse-translated into innovative in-vitro and mouse models closely mimicking the human disease. This will allow a profound study of the mechanistic basis of treatment failure by deciphering the complex network between components of the microenvironment and cancer cells leading to increased resistance to chemotherapy and infiltrative growth along adjacent lymphatic and neural structures as well as metastatic spread. Identification of cancer (stem) cell-autonomous as well as stromal-derived mediators of invasion and chemoresistance will lead to novel drug targets to overcome the current therapeutic dilemma. The consortium has been specifically designed to include all required levels of expertise: 1) surgical and medical oncology groups conducting the largest clinical trials for pancreatic cancer in Europe, 2) expert pancreatic pathologists, 3) basic scientists focused on the study of carcinogenesis and tumour microenvironment interactions in the pancreas, 4) molecular oncology groups that have developed genetically engineered mouse models faithfully recapitulating human pancreatic cancer, as well as 5) pharmaceutical industry specialised on drug development.