Autocrine semaphorin 3A signaling promotes glioblastoma dispersal.
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.
Bagci
T
T
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 2111, USA.
Wu
J K
JK
Pfannl
R
R
Ilag
L L
LL
Jay
D G
DG
D019898:Autocrine Communication / Q000502:physiology*; D001923:Brain Chemistry; D001932:Brain Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D039942:Neuropilin-1 / Q000502:physiology; D040901:Proteomics; D040121:Semaphorin-3A / Q000032:analysis / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology
C107953:RAC1 protein, human; C108639:SEMA3A protein, human; D040121:Semaphorin-3A; D039942:Neuropilin-1; D020830:rac1 GTP-Binding Protein