Final Report Summary - PA-CSC (Molecular characterization and targeted elimination of metastatic pancreatic cancer stem cells)
Pancreatic adenocarcinoma is the deadliest solid cancer and currently the fourth most frequent cause for cancer-related deaths with the incidence is still on the rise and expected to become the 2nd most frequent cause of cancer-related death by 2020. Despite increasing research activities in the field of pancreatic tumour and vascular biology, there has hardly been any substantial therapeutic progress regarding clinical endpoints over the past decades. However, new hope has been generated by the re-emerging concept that malignancies, including pancreatic cancer may arise from cancer stem cells that bear physiological properties of stem cells. We have provided evidence that these cells also exist in the pancreas and characterized their heterogeneity with respect to metastatic activity and resistance to chemotherapy. Building on these earlier studies from our lab and during the course of the present ERC-funded project we have now performed comprehensive (epi-)genetic and metabolic analyses of highly purified cancer stem cells, their more differentiated progenies, normal tissue resident stem cells from mouse and man. The subsequent functional characterization of newly identified genes and their biological functions in respect to tumour angiogenesis, invasiveness, and metastasis for (pancreatic) cancer provided novel insights into the role of cancer stem cells in pancreatic cancer biology and putative novel therapeutic avenues. In addition, we have studied the role of risk factors, i.e. smoking, for the development and progression of pancreatic cancer. Our data demonstrate a crucial role for nicotine in enhancing the susceptibility of the exocrine pancreas for transforming events, e.g. mutant K-Ras. We have also made significant progress in our understanding of the tumour microenvironment as a source for pro-cancer stem cell factors. We discovered an intricate relationship between cancer stem cells and tumour-associated macrophages, which results in enhanced stemness and chemoresistance. Finally, we discovered a distinct metabolic phenotype for pancreatic cancer stem cells with high susceptibility to mitochondrial targeting. Together, our experiments generated important clues how cancer stem cells circumvent the physiological regulatory elements of stem cell functionality, interact with the tumour microenvironment and, even more importantly, how these cells escape the response to standard cancer therapy. Based on these novel findings we have been able to develop innovative targeted and multimodal treatment modalities for the successful elimination of these cells as the previously unrecognized root of pancreatic cancer. Some of these treatment approaches are now in the process of being translated into early phase clinical trials for patients with localized and advanced pancreatic cancer, respectively. Thus, all prespecified milestones for this project have been reached.