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Head and Neck Cancer-derived small extracellular vesicles sensitize TRPV1+ neurons to mediate cancer pain

Kufreobong E. Inyang, Christine M. Evans, Matthew Heussner, Margaret Petroff, Mark Reimers, Paola D. Vermeer, Nathan Tykocki, View ORCID ProfileJoseph K. Folger, View ORCID ProfileGeoffroy Laumet
doi: https://doi.org/10.1101/2022.09.06.506411
Kufreobong E. Inyang
1Department of Physiology, Michigan State University, East Lansing, MI, USA
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Christine M. Evans
1Department of Physiology, Michigan State University, East Lansing, MI, USA
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Matthew Heussner
1Department of Physiology, Michigan State University, East Lansing, MI, USA
2College of Osteopathic Medicine, Michigan State University, East Lansing, MI
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Margaret Petroff
3Department of Pathology Michigan State University College of Veterinary Medicine, East Lansing, MI
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Mark Reimers
1Department of Physiology, Michigan State University, East Lansing, MI, USA
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Paola D. Vermeer
4Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, South Dakota
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Nathan Tykocki
5Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI
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Joseph K. Folger
1Department of Physiology, Michigan State University, East Lansing, MI, USA
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Geoffroy Laumet
1Department of Physiology, Michigan State University, East Lansing, MI, USA
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  • ORCID record for Geoffroy Laumet
  • For correspondence: laumetge@msu.edu
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Summary

Severe pain is often experienced by patients with head and neck cancer and is associated with a poor prognosis. Despite its frequency and severity, current treatments fail to adequately control cancer-associated pain, because of our lack of mechanistic understanding. Cancer-derived small extracellular vesicles (Cancer-sEVs) are well- positioned to function as mediators of communication between cancer cells and neurons. Inhibition of Cancer-sEV release attenuated pain in tumor-bearing mice. Injection of purified Cancer-sEVs is sufficient to induce pain hypersensitivity in naïve mice. Cancer-sEVs triggered calcium influx in nociceptors and inhibition or ablation of nociceptors protect against cancer pain. Interrogation of published sequencing data of human sensory neurons exposed to human Cancer-sEVs suggested a stimulation of protein translation in neurons. Induction of translation by Cancer-sEVs was validated in our mouse model and its inhibition alleviated cancer pain in mice. These findings define a role of Cancer-sEVs in cancer pain and identify several druggable targets.

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Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 08, 2022.
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Head and Neck Cancer-derived small extracellular vesicles sensitize TRPV1+ neurons to mediate cancer pain
Kufreobong E. Inyang, Christine M. Evans, Matthew Heussner, Margaret Petroff, Mark Reimers, Paola D. Vermeer, Nathan Tykocki, Joseph K. Folger, Geoffroy Laumet
bioRxiv 2022.09.06.506411; doi: https://doi.org/10.1101/2022.09.06.506411
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Head and Neck Cancer-derived small extracellular vesicles sensitize TRPV1+ neurons to mediate cancer pain
Kufreobong E. Inyang, Christine M. Evans, Matthew Heussner, Margaret Petroff, Mark Reimers, Paola D. Vermeer, Nathan Tykocki, Joseph K. Folger, Geoffroy Laumet
bioRxiv 2022.09.06.506411; doi: https://doi.org/10.1101/2022.09.06.506411

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