PTCH1-null induced pluripotent stem cells exclusively differentiate into immature ectodermal cells with large areas of medulloblastoma-like tissue.

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with an increased incidence of tumors, such as basal cell carcinomas and medulloblastomas. The PTCH1 gene, responsible for NBCCS, suppresses the hedgehog signaling pathway, which is recognized as one of the important pathways in tumorigenesis and, thus, is a therapeutic target in cancer. In the present study, we generated PTCH1 induced pluripotent stem cells (iPSCs) from NBCCS patient-derived iPSCs (PTCH1) by gene editing. The proliferation of PTCH1 iPSCs was accelerated due to the activation of the hedgehog signaling pathway. When PTCH1 iPSCs were subcutaneously injected into immunodeficient mice, the resulting teratomas almost exclusively contained immature ectodermal lineage cells expressing medulloblastoma markers, and the percentages of the area occupied by medulloblastoma-like tissue were larger in PTCH1 teratomas than in PTCH1 teratomas. In contrast, in PTCH1 teratomas, medulloblastoma-like tissue positive for all of these medulloblastoma markers was not observed. The present results indicate the importance of PTCH1 in medulloblastoma formation and the suitability of these gene-edited iPSCs and PTCH1 teratomas as models for the formation of tumors, such as medulloblastomas and Hh-related tumors.