Prokineticin signaling is required for the maintenance of a de novo population of c-KIT+ cells to sustain neuroblastoma progression

Abstract

High cellular heterogeneity within neuroblastomas (NBs) may account for the non-uniform response to treatment. c-KIT+ cells are frequently detected in NB, but how they influence NB behavior still remains elusive. Here, we used NB tumor-initiating cells to reconstitute NB development and demonstrated that c-KIT+ cells are de novo generated and dynamically maintained within the tumors to sustain tumor progression. c-KIT+ NB cells express higher levels of neural crest and stem cell markers (SLUG, SOX2 and NANOG) and are endowed with high clonogenic capacity, differentiation plasticity and are refractory to drugs. With serial transplantation assays, we found that c-KIT expression is not required for tumor formation, but c-KIT+ cells are more aggressive and can induce tumors ninefold more efficiently than c-KIT−/low cells. Intriguingly, c-KIT+ cells exhibited a long-term in vivo self-renewal capacity to sustain the formation of secondary and tertiary tumors in mice. In addition, we showed that Prokineticin signaling and mitogen-activated protein kinase pathways are crucial for the maintenance of c-KIT+ cells in tumor to promote NB progression. Our results highlight the importance of this de novo population of NB cells in sustainable growth of NB and reveal specific signaling pathways that may provide targets leading to more effective NB therapies.