Cancer exosomes induce tumor innervation

Marianna Madeo, Paul L. Colbert, Daniel W. Vermeer, Christopher T. Lucido, Jacob T. Cain, Elisabeth G. Vichaya, Aaron J. Grossberg, Desi Rae Muirhead, Alex P. Rickel, Zhongkui Hong, Jing Zhao, Jill M. Weimer, William C. Spanos, John H. Lee, Robert Dantzer, Paola D. Vermeer

Research output: Contribution to journalArticlepeer-review

164 Scopus citations


Patients with densely innervated tumors suffer with increased metastasis and decreased survival as compared to those with less innervated tumors. We hypothesize that in some tumors, nerves are acquired by a tumor-induced process, called axonogenesis. Here, we use PC12 cells as an in vitro neuronal model, human tumor samples and murine in vivo models to test this hypothesis. When appropriately stimulated, PC12 cells extend processes, called neurites. We show that patient tumors release vesicles, called exosomes, which induce PC12 neurite outgrowth. Using a cancer mouse model, we show that tumors compromised in exosome release are less innervated than controls. Moreover, in vivo pharmacological blockade of exosome release similarly attenuates tumor innervation. We characterize these nerves as sensory in nature and demonstrate that axonogenesis is potentiated by the exosome-packaged axonal guidance molecule, EphrinB1. These findings indicate that tumor released exosomes induce tumor innervation and exosomes containing EphrinB1 potentiate this activity.

Original languageEnglish (US)
Article number4284
JournalNature communications
Issue number1
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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