Novel ciliary regulation loops in Hedgehog-dependent tumor entities

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Hedgehog (HH) signaling implements a plethora of biological effects in development and tumorigenesis ranging from cell proliferation to cell differentiation. Despite the great importance of this signaling system in physiology and pathology, several key steps in the signaling cascade are still only poorly understood. Particularly in light of a future clinical tumor therapy, the understanding of novel HH regulatory circuits and the evaluation of possible drug targets is of high significance. In our own preliminary work, we were able to identify novel positive factors in the HH pathway, which are overexpressed in HH-dependent malignancies. These effects are evoked by the ligand-driven import of these proteins into the primary cilium, a cellular organelle crucial for proper HH signaling. In the proposed project, we aim to characterize these newly identified ciliary signaling molecules on a mechanistic and functional level. We would like to understand which ciliary events are activated by these proteins and which impact these processes have on HH-induced medulloblastoma formation. To address these issues, we will apply a diverse set of in vitro approaches, genetic knock-out animals as well as murine tumor models.