Tumor-infiltrating nerves create an electro-physiologically active microenvironment and contribute to treatment resistance

Kovacs, A.; Vermeer, D. W.; Madeo, M.; Vermeer, S. J.; Williamson, C. S.; Rickel, A.; Stamp, J.; Lucido, C. T.; Cain, J.; Bell, M.; Morgan, M.; Yoon, J.-Y.; Mitchell, M. A.; Tulina, N.; Stuckelberger, S.; Budina, A.; Orman, D.; Jung, E.; Schwartz, L. E.; Eichwald, T.; Hong, Z.; Weimer, J.; Hooper, J. E.; Godwin, A. K.; Talbot, S.; Drapkin, R.; Vermeer, P. D.

doi:10.1101/2020.04.24.058594

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bioRxiv · 10.1101/2020.04.24.058594

Tumor-infiltrating nerves create an electro-physiologically active microenvironment and contribute to treatment resistance

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Abstract

Patients with densely innervated tumors do poorly as compared to those with sparsely innervated disease. Why some tumors heavily recruit nerves while others do not, remains unknown as does the functional contribution of tumor-infiltrating nerves to cancer. Moreover, while patients receive chemotherapeutic treatment, whether these drugs affect nerve recruitment has not been tested. Using a murine model of ovarian cancer, we show that tumor-infiltrating sensory nerves potentiate tumor growth, decrease survival, and contribute to treatment resistance. Furthermore, matched patient samples show significantly increased tumor innervation following chemotherapy. In vitro analysis of tumor-released extracellular vesicles (sEVs) shows they harbor neurite outgrowth activity. These data suggest that chemotherapy may alter sEV cargo, endowing it with robust nerve recruiting capacity.

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Kovacs, A., Vermeer, D. W., Madeo, M., Vermeer, S. J., Williamson, C. S., Rickel, A., Stamp, J., Lucido, C. T., Cain, J., Bell, M., Morgan, M., Yoon, J.-Y., Mitchell, M. A., Tulina, N., Stuckelberger, S., Budina, A., Orman, D., Jung, E., Schwartz, L. E., Eichwald, T., Hong, Z., Weimer, J., Hooper, J. E., Godwin, A. K., Talbot, S., Drapkin, R., Vermeer, P. D.. 2020-04-25. Tumor-infiltrating nerves create an electro-physiologically active microenvironment and contribute to treatment resistance. https://doi.org/10.1101/2020.04.24.058594

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