Opening new doors: Hedgehog signaling and the pancreatic cancer stroma

In pancreatic cancer, a very difficult to treat tumor type with a dismal prognosis, Hedgehog (Hh) ligands are produced by tumor cells and signal to the surrounding tumor microenvironment. This thesis gives new insights into the different aspects of stromal biology and Hh signaling by describing for example that localization of Smoothened (Smo) in fibroblasts to different cellular compartments, especially the primary cilium, can separate the signaling output into either transcriptional or migratory responses. Furthermore, to get a better insight into the transcriptional response, we investigate which genes are upregulated in the stromal compartment in response to Hh ligands and relate these to poor clinical outcome in pancreatic cancer patients. We also look into new mechanisms of Hh ligand spreading from tumor cells, by defining the role of ADAM metalloproteases in the release of Hh from pancreatic cancer cells. In one chapter we focus on a specific ADAM gene and show that ADAM12 is overexpressed in the pancreatic cancer stroma, associates with poor clinical outcome and can be detected in the serum of pancreatic cancer patients, making it an interesting biomarker for stromal activation. Throughout the thesis we also describe the establishment and use of newly developed patient-derived xenograft and primary cell lines models, to gain better insight into the pathobiology of this disease. The research in this thesis therefore explores many different layers of the regulation of both the Hh signaling pathway specifically, and the stromal response in general, in pancreatic cancer.