Hedgehog signaling plays a dual role in pancreatic carcinogenesis

The hedgehog (Hh) pathway plays an important role in a wide variety of developmental processes including cellular differentiation and tissue patterning. While Hh signaling is a critical component of embryonic development, this pathway is not typically active in most adult tissues. Inappropriate Hh signaling has been associated with several types of malignancies including pancreatic ductal adenocarcinoma (PDAC). In PDAC, the Hh pathway is activated by two distinct mechanisms in the tumor epithelial and stromal compartments. In the stroma, the Hh pathway activity is induced by its ligands in a canonical fashion; in tumor epithelial cells its activity is regulated in a ligand-independent manner by known PDAC oncogenic cascades including KRAS, TGFß, and EGFR signaling. Initial preclinical studies demonstrated that the Hh pathway may be a promising therapeutic target for PDAC. However, Hh inhibition has not been successful in clinical trials of PDAC patients with advanced metastatic disease. Recent reports indicate the Hh pathway may play a dual role in carcinogenesis, acting as an oncogene in early tumorigenesis while switching to a tumor suppressor as the cancer progresses. Current research efforts are aimed at further understanding the role of the Hh pathway in all stages of carcinogenesis and defining the translational value of Hh inhibition in PDAC.