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Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

Oncogene volume 28, pages 3537–3550 (2009)Cite this article

Abstract

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.

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Acknowledgements

We thank Alex Kolodkin (Johns Hopkins School of Medicine) for kindly providing function blocking anti-Nrp-1 antibody; Jean Stewart, Dean Yimlamai and Jennifer Salluzzo for technical help; Sonya Craig for discussions about the adhesion assay; Brenda Eustace for assistance with the invasion screen; Pat Hibberd for help with the statistical analysis; Laura Liscum, Tamer Onder and Jessica McCready for critically reading the paper. This work was supported by the Goldhirsh Foundation and the NIH, RO1 CA 116642.

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Authors and Affiliations

  1. Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA

    T Bagci & D G Jay

  2. Department of Neurosurgery, Tufts University School of Medicine, Boston, MA, USA

    J K Wu

  3. Department of Neuropathology, Tufts University School of Medicine, Boston, MA, USA

    R Pfannl

  4. Patrys Ltd., Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia

    L L Ilag

  5. Department of Physiology, Tufts University School of Medicine, Boston, MA, USA

    D G Jay

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Correspondence to D G Jay.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Bagci, T., Wu, J., Pfannl, R. et al. Autocrine semaphorin 3A signaling promotes glioblastoma dispersal. Oncogene 28, 3537–3550 (2009). https://doi.org/10.1038/onc.2009.204

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