Glioblastoma multiforme (GBM) is the most malignant glioma type with diffuse 
borders due to extensive tumor cell infiltration. Therefore, understanding the 
mechanism of GBM cell dispersal is critical for developing effective therapies 
to limit infiltration. We identified neuropilin-1 as a mediator of cancer cell 
invasion by a functional proteomic screen and showed its role in GBM cells. 
Neuropilin-1 is a receptor for semaphorin3A (Sema3A), a secreted chemorepellent 
that facilitates axon guidance during neural development. Although neuropilin-1 
expression in GBMs was previously shown, its role as a Sema3A receptor remained 
elusive. Using fluorophore-assisted light inactivation and RNA interference , we 
showed that neuropilin-1 is required for GBM cell migration. We also showed that 
GBM cells secrete Sema3A endogenously, and RNA interference-mediated 
downregulation of Sema3A inhibits migration and alters cell morphology that is 
dependent on Rac1 activity. Sema3A depletion also reduces dispersal, which is 
recovered by supplying Sema3A exogenously. Extracellular application of Sema3A 
decreases cell-substrate adhesion in a neuropilin-1-dependent manner. Using 
immunohistochemistry, we showed that Sema3A is overexpressed in a subset of 
human GBMs compared with the non-neoplastic brain. Together, these findings 
implicate Sema3A as an autocrine signal for neuropilin-1 to promote GBM 
dispersal by modulating substrate adhesion and suggest that targeting 
Sema3A-neuropilin-1 signaling may limit GBM infiltration.