Molecular understanding of Hedgehog-dependent cancers From pathways to patients

Hedgehog-dependent cancers make up a large fraction of all cancers diagnosed worldwide. Aberrant activation of the Hedgehog (Hh) signaling pathway occurs in malignancies of the breast, lungs, stomach, skin and pancreas. Around 340.000 new cases of pancreatic cancer (PDAC) are diagnosed yearly, almost none of which are cured. Basal cell carcinoma (BCC) occurs at much higher incidences, but this disease is rarely fatal. The causes of Hh pathway activation mechanisms differ between BCC and PDAC, and both diseases were studied in this thesis to unravel the underlying mechanisms. The focus of this thesis was mostly on PDAC. Besides providing an in-depth analysis of Hh pathway regulation, we have also identified proteins that are regulated by the Hh pathway and are important for tumor growth in PDAC. Furthermore, we have identified clinically relevant molecular subgroups in PDAC, of which the therapeutic vulnerabilities were revealed. Additionally we have established the clonal dynamics that underlie tumor growth in our in vivo models for PDAC.