Plasticity in Neuroblastoma Cell Identity Defines a Noradrenergic-to-Mesenchymal Transition (NMT)

SIMPLE SUMMARY: Neuroblastoma arises in the developing sympathetic nervous system and represents the most common extracranial pediatric solid tumor. High-risk patients often experience relapse despite intensive multimodal therapies. Consistent with previous reports describing various phenotypes in neuroblastoma cell lines, recent studies precisely characterized two distinct cell identities based on transcriptomic and epigenetic profiles. In this review, we focus on the description of these two cell states, which we define as noradrenergic (NOR) and mesenchymal (MES), and discuss the plasticity between them. The differences in chemoresistance and invasion/migration properties of these two identities may have important clinical relevance. Deciphering the mechanisms of transdifferentiation from a NOR to a MES identity, which is reminiscent of the well-known epithelial-to-mesenchymal transition, is a key step to better understand neuroblastoma biology and improve therapeutic management of patients. ABSTRACT: Neuroblastoma, a pediatric cancer of the peripheral sympathetic nervous system, is characterized by an important clinical heterogeneity, and high-risk tumors are associated with a poor overall survival. Neuroblastoma cells may present with diverse morphological and biochemical properties in vitro, and seminal observations suggested that interconversion between two phenotypes called N-type and S-type may occur. In 2017, two main studies provided novel insights into these subtypes through the characterization of the transcriptomic and epigenetic landscapes of a panel of neuroblastoma cell lines. In this review, we focus on the available data that define neuroblastoma cell identity and propose to use the term noradrenergic (NOR) and mesenchymal (MES) to refer to these identities. We also address the question of transdifferentiation between both states and suggest that the plasticity between the NOR identity and the MES identity defines a noradrenergic-to-mesenchymal transition, reminiscent of but different from the well-established epithelial-to-mesenchymal transition.