Abstract
Neuroblastomas are the most common extracranial solid tumors in children and arise from the embryonic neural crest. MYCN-amplification is a feature of ∼30% of neuroblastoma tumors and portends a poor prognosis. Neural crest precursors undergo epithelial-to-mesenchymal transition (EMT) to gain migratory potential and populate the sympathoadrenal axis. Neuroblastomas are posited to arise due to a blockade of neural crest differentiation. We have recently reported effects of a novel MET inducing compound ML327 (N-(3-(2-hydroxynicotinamido) propyl)-5-phenylisoxazole-3-carboxamide) in colon cancer cells. Herein, we hypothesized that forced epithelial differentiation using ML327 would promote neuroblastoma differentiation. In this study, we demonstrate that ML327 in neuroblastoma cells induces a gene signature consistent with both epithelial and neuronal differentiation features with adaptation of an elongated phenotype. These features accompany induction of cell death and G1 cell cycle arrest with blockage of anchorage-independent growth and neurosphere formation. Furthermore, pretreatment with ML327 results in persistent defects in proliferative potential and tumor-initiating capacity, validating the pro-differentiating effects of our compound. Intriguingly, we have identified destabilization of MYC signaling as an early and consistent feature of ML327 treatment that is observed in both MYCN-amplified and MYCN-single copy neuroblastoma cell lines. Moreover, ML327 blocked MYCN mRNA levels and tumor progression in established MYCN-amplified xenografts. As such, ML327 may have potential efficacy, alone or in conjunction with existing therapeutic strategies against neuroblastoma. Future identification of the specific intracellular target of ML327 may inform future drug discovery efforts and enhance our understanding of MYC regulation.
Highlights
Neuroblastomas are the most common extracranial solid tumors in children, accounting for 10% of cancerrelated deaths in children [1]
The remaining viable neuroblastoma tissue was poorly differentiated (Figure 5F). These findings suggest that ML327 suppresses MYCN levels within neuroblastoma xenografts and induces cell death within xenografts
We hypothesized that ML327, an mesenchymal-to-epithelial transition (MET) induction agent identified in epithelial carcinomas, would elicit antitumorigenic effects in neural crest-derived neuroblastomas
Summary
Neuroblastomas are the most common extracranial solid tumors in children, accounting for 10% of cancerrelated deaths in children [1]. Neural crest precursors develop from the dorsal neural tube, where the cells undergo epithelial-mesenchymal transition (EMT) to gain migratory potential and populate the sympathetic nervous system [3, 6]. This process is characterized by loss of E-cadherin within adherens junctions and destabilization of tight junctions that mediate cell adhesion. Post-migratory neural crest cells express high levels of N-MYC, where it regulates the ventral migration and expansion of neural crest cells [6]. Aberrantly high N-MYC is thought to contribute to neuroblastoma tumorigenesis at least in part by promoting a persistent mesenchymal phenotype within neuroblastomas
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