SEMA3C Depletion Promotes Neuroblastoma Metastatic Dissemination

Neuroblastoma is a pediatric cancer of embryonic origin, arising from sympatho-adrenal neural crest cells. Developing adequate neuroblastoma models has proven difficult, as the embryonic context makes recapitulation of early tumorigenic events challenging. To overcome this limitation, Delloye-Bourgeois and colleagues developed an embryonic avian model of neuroblastoma by grafting neuroblastoma cells into chick embryos. The majority of cells migrated away from the graft site to sites targeted by endogenous sympatho-adrenal neural crest cells, and the neuroblastoma cells and endogenous neural crest cells exhibited common migration patterns. Once at the target site, neuroblastoma cells initiated tumorigenesis, and the model recapitulated human tumors. Further, neuroblastoma metastasis occurred in this avian model, with secondary dissemination occurring via the aorta and peripheral nerves. To identify genes that might regulate metastasis, RNA sequencing was performed on naïve neuroblastoma cells and cells that had formed tumors in the chick embryo. The semaphorin (SEMA) family of genes, which are involved in regulating axon and cell migration, were differentially expressed. Specifically, SEMA3C was downregulated in the grafts, suggesting that its loss of expression may trigger metastasis. Depletion of SEMA3C resulted in grafted embryos with tumor cells dispersed throughout the embryonic tissue, whereas control cells remained tightly condensed. Inducible depletion of SEMA3C in established chick embryo tumors resulted in neuroblastoma cell detachment and metastatic dissemination. SEMA3C depletion reduced cell cohesion to promote metastasis in a dose-dependent manner. Further, patient-derived chick embryo xenografts were generated from localized and metastatic neuroblastomas. Metastatic dissemination along peripheral nerves and within the aorta was observed only in the metastatic samples. In addition to developing an embryonal model to study early neuroblastoma tumorigenesis and metastasis, these findings identify SEMA3C as a regulator of metastatic dissemination.

Delloye-Bourgeois C, Bertin L, Thoinet K, Jarrosson L, Kindbeiter K, Buffet T, et al. Microenvironment-driven shift of cohesion/detachment balance within tumors induces a switch toward metastasis in neuroblastoma. Cancer Cell 2017;32:427–43.e8.

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