Coexpression of MYCN and ALK Induces Neuroblastoma-Like Tumors From Human iPS Cell-Derived Cranial Neural Crest Cells [Microarray]

Neuroblastoma is a pediatric solid tumor originating from neural crest cells, which are precursors of the sympathetic nervous system. Amplification of MYCN proto-oncogene is a key factor contributing to poor prognosis of neuroblastoma and is strongly associated with aggressive disease progression. Additionally, the anaplastic lymphoma kinase plays an important role in the pathogenesis of neuroblastoma. Mutation or amplification of anaplastic lymphoma kinase drives oncogenic signaling pathways, such as the MAPK and Ras pathways, which together with MYCN amplification exacerbate tumor malignancy. The use of human induced pluripotent stem cell-derived cranial neural crest cells to establish a neuroblastoma model is expected to be of great significance in studying the pathogenesis of this disease. In this study, we sought to mimic the tumorigenic process of neuroblastoma by overexpressing MYCN and anaplastic lymphoma kinase in cranial neural crest cells derived from human induced pluripotent stem cells. These modified cells when subcutaneously transplanted into immunodeficient mice induced neuroblastoma-like tumors, and could thus be used an in vitro model to study this cancer. Through extensive gene expression profiling and whole exome sequencing of MYCN/anaplastic lymphoma kinase-induced clones, we identified key features of neuroblastoma, including activation of the MAPK signaling pathway and gain of 17q chromosome, which is critical for malignant tumor development. This model provides a valuable platform for studying the biological mechanisms driving anaplastic lymphoma kinase mutations and MYCN amplification in neuroblastoma derived from cranial neural crest cells as well as for exploring potential therapeutic approaches against these targets to improve patient prognosis.