SMO and cancer: There are several key mechanisms in tumorigenesis that may involve Hh/GLI signaling [11], [13]; first, inactivating mutations in the negative regulators PTCH or SUFU, or activating mutations in the positive regulator SMO cause pathway activation in a cell-autonomous and Hh ligand independent manner [5], [26]–[28]; secondly, ligand-dependent autocrine mechanisms in which cancer cells both secrete and respond to Hh ligands causing cell-autonomous pathway activation [29], [30]; thirdly, paracrine mechanisms in which stromal cells are induced by Hh producing cancer cells [31]–[34].