Neuropilin-2 acts as a modulator of Sema3A-dependent glioma cell migration.

Semaphorin 3A (Sema3A) is a secreted guidance molecule initially described in the nervous system. This protein is able to control axon growth but also effects on endothelial cells migration. Here, we report that Sema3A acts as a chemorepellent factor for the rat C6 glioma cells and three different human glioma cell lines. Interestingly, Sema3A triggered a chemoattractive response in a fourth human glioma cell line. The nature of the receptor complex ensuring the appropriate signaling was dissected in C6 cells by using function blocking antibodies and gain- or loss-of function experiments using recombinant receptors. Our results demonstrate that neuropilin-1, neuropilin-2 and PlexinA1 are necessary to trigger cell repulsion. The selective blockade of neuropilin-1 or Plexin-A1 switched the chemorepulsive effect of Sema3A into a chemoattractive one. Strikingly, blocking Neuropilin-2 suppressed Sema3A-induced cell migration while overexpression of neuropilin-2 was able to convert the chemorepulsive effect of Sema3A into a chemoattractive one. Our results not only provide additional evidence for a biological function of Sema3A in glioma migration but also reveal part of the receptor complex involved. Hence, our study describes a receptor-based plasticity in cancer cells leading to opposite migration behavior in response to the same extracellular signal.