From Neuroblastoma to Neurons: Halting Cancer Migration In Vivo

Ankur Saxena, PhD
Neuroblastoma (NB) is the most common cancer in the first year of life and is derived from the neural crest (NC), a highly migratory stem cell population that gives rise to many cell types including neurons, glia, and melanocytes. Despite neural crest cells (NCCs) migrating and differentiating throughout the embryo, including making major contributions to the developing head, NB is found almost exclusively within just the abdomen and thorax. Intriguingly, NB in young patients exhibits a high rate of spontaneous resolution, whereby malignant cells, for reasons that remain unclear, often differentiate into non-malignant neurons and/or undergo apoptosis. We hypothesized that spontaneous resolution might play a role in NB’s trunk-biased localization and devised an in vivo experimental system to test this idea. First, we demonstrated that multiple human NB cell lines, when injected into zebrafish embryos, migrated in a strikingly coordinated fashion with native NCCs. We next injected only NB cells previously shown to be incapable of differentiating into neurons in vitro and found that they rapidly differentiated in vivo upon migration into the developing head. We followed up by demonstrating the in vivo differentiating potential of retinoic acid, a commonly used but poorly understood therapeutic agent for NB patients, and intersectin-1, a scaffolding protein with known tumorigenic properties. Taken together, our findings suggest a novel explanation for NB’s trunk-biased localization in young patients and highlight the potential of neurogenic microenvironment-induced differentiation and specific signaling pathways in promoting the resolution of NB in vivo.