N-myc induces transformation of neural crest stem cells in vitro and in vivo

Abstract

Cumulating evidence suggests that neuroblastoma (NB) originates from neural crest stem cells (NCSC) of the sympathoadrenal lineage. Pluripotency of NCSC is documented by the ability to differentiate into muscle cells, chromaffin cells, neurons and glial cells, as well as melanocytes, cartilage and bone. To characterize the NCSC population, a cell line is required that can be maintained for many passages, and which retains pluripotency as well as self renewal capacity. We previously established a multipotent NCSC line, JoMa1, which is kept in an undifferentiated state by conditional expression of c-Myc and which can be differentiated into the above mentioned cell types. N-myc has been shown to promote cell cycle progression in NB cells in vitro and transgenic overexpression of N-myc is sufficient to induce neuroblastoma-like tumors in mice. Still, the origin of neuroblastoma could not be clearly assigned to a defined cell population. To address this question, we established JoMa1 cells with stable ectopic expression of N-Myc. JoMa1-Nmyc were able to grow in cell culture without depending on c-myc expression. Subcutaneous injection of JoMa1-Nmyc into nude mice caused the formation of NB-like tumors. Interestingly, treatment of xenografted JoMa1 using a Myc-inhibitor inhibited cell proliferation in vitro. Thus, we here show for the first time that transformed NCSC cells can give rise to neuroblastic tumors and support the notion that NCSC are the precursor cells of neuroblastoma. We now aim to characterize the tumorigenicity of JoMa1-Nmyc in a syngeneic mouse model and to identify the genomic changes caused by N-myc driven transformation of JoMa1.