Functional neuronal circuits promote disease progression in cancer

Sci Adv. 2023 May 10;9(19):eade4443. doi: 10.1126/sciadv.ade4443. Epub 2023 May 10.


The molecular and functional contributions of intratumoral nerves to disease remain largely unknown. We localized synaptic markers within tumors suggesting that these nerves form functional connections. Consistent with this, electrophysiological analysis shows that malignancies harbor significantly higher electrical activity than benign disease or normal tissues. We also demonstrate pharmacologic silencing of tumoral electrical activity. Tumors implanted in transgenic animals lacking nociceptor neurons show reduced electrical activity. These data suggest that intratumoral nerves remain functional at the tumor bed. Immunohistochemical staining demonstrates the presence of the neuropeptide, Substance P (SP), within the tumor space. We show that tumor cells express the SP receptor, NK1R, and that ligand/receptor engagement promotes cellular proliferation and migration. Our findings identify a mechanism whereby intratumoral nerves promote cancer progression.

MeSH terms

  • Animals
  • Breast Neoplasms* / epidemiology
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Human Papillomavirus Viruses
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Neurons* / pathology
  • Ovarian Neoplasms* / epidemiology
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / secondary
  • Ovary / innervation
  • Specific Pathogen-Free Organisms
  • Squamous Cell Carcinoma of Head and Neck* / metabolism
  • Squamous Cell Carcinoma of Head and Neck* / pathology
  • Squamous Cell Carcinoma of Head and Neck* / virology
  • Substance P / metabolism
  • Survival Analysis


  • Substance P