Conditional Activation of c-MYC in Distinct Catecholaminergic Cells Drives Development of Neuroblastoma or Somatostatinoma

Abstract

c-MYC is an important driver of high-risk neuroblastoma. A lack of c-MYC–driven genetically engineered mouse models (GEMM) has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and to develop effective therapies. Here, we showed that conditional c-MYC induction via Cre recombinase driven by a tyrosine hydroxylase (Th) promoter led to a preponderance of PDX1+ somatostatinoma, a type of pancreatic neuroendocrine tumor (PNET). However, c-MYC activation via an improved Cre recombinase driven by a dopamine β-hydroxylase (Dbh) promoter resulted in neuroblastoma development. The c-MYC murine neuroblastoma tumors recapitulated the pathologic and genetic features of human neuroblastoma and responded to anti-GD2 immunotherapy and DFMO, an FDA-approved inhibitor targeting the MYC transcriptional target ODC1. Thus, c-MYC overexpression results in different but related tumor types depending on the targeted cell. The GEMMs represent valuable tools for testing immunotherapies and targeted therapies for these diseases.