Establishment of a Gorlin syndrome model from induced neural progenitor cells exhibiting constitutive GLI1 expression and high sensitivity to inhibition by smoothened (SMO)

The hedgehog signaling pathway is a vital factor for embryonic development and stem cell maintenance. Dysregulation of its function results in tumor initiation and progression. The aim of this research was to establish a disease model of hedgehog-related tumorigenesis with Gorlin syndrome-derived induced pluripotent stem cells (GS-iPSCs). Induced neural progenitor cells from GS-iPSCs (GS-NPCs) show constitutive high GLI1 expression and higher sensitivity to smoothened (SMO) inhibition compared with wild-type induced neural progenitor cells (WT-NPCs). The differentiation process from iPSCs to NPCs may have similarity in gene expression to Hedgehog signal-related carcinogenesis. Therefore, GS-NPCs may be useful for screening compounds to find effective drugs to control Hedgehog signaling activity. The hedgehog pathway is pivotal in basal cell carcinoma and medulloblastoma development. Gorlin syndrome-derived, induced pluripotent stem cells (iPSCs) carrying a heterozygous mutation in PTCH1, a hedgehog target gene, exhibited high GLI1 expression and enhanced sensitivity to a hedgehog pathway inhibitor after neural differentiation. These iPSCs can serve as a model for hedgehog pathway-related tumors.