Differential susceptibility to pathway activation in postnatal progenitor/stem cells during Hedgehog induced tumorigenesis. Free

LB-96

Deregulation of Hedgehog (Hh) pathway activity has been associated with a wide range of human cancers. Our recent study has also established a novel robust somatic mouse model of Hh related sporadic tumors, including medulloblastoma, basal cell carcinoma (BCC), and rhabdomyosarcoma. Despite the growing evidence of Hh's role in the function of different postnatal progenitor/stem cells, the regulation of pathway activation in these cells during tumorigenesis is still poorly understood. To further address this question, we first expressed SmoM2, an activated mutant of Smoothened, in Hh responding progenitor/stem cells at different time points in postnatal mice to examine the temporal regulation of Hh-induced tumorigenesis. Further lineage-specific analysis revealed that up-regulation of Hh activity in postnatal committed progenitors in cerebellum and skin hair follicles was able to generate medulloblastoma and BCC, while constitutive pathway activation in Hh-responding postnatal CNS stem cells and muscle progenitors failed to induce tumor formation, suggesting a possible cell-intrinsic susceptibility to Hh activation during cellular transformation.