biostudies-literatureInyang KENational Institute of Neurological Disorders and StrokeNIDCR NIH HHSNINDS NIH HHSNational Institute of Dental and Craniofacial ResearchRita Allen Foundation608-620https://www.ebi.ac.uk/biostudies/studies/S-EPMC10915104biostudies-literatureUnknown165(3)<h4>Abstract</h4>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. Although recent works have shed some light of the biology underlying pain in HPV-negative oral cancers, the mechanisms mediating pain in HPV+ cancers remain unknown. 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 naive mice that is prevented by QX-314 treatment and in Trpv1-/- mice. Cancer-sEVs triggered calcium influx in nociceptors, and inhibition or ablation of nociceptors protects 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. In summary, our work reveals that HPV+ head and neck squamous cell carcinoma-derived sEVs alter TRPV1+ neurons by promoting nascent translation to mediate cancer pain and identified several promising therapeutic targets to interfere with this pathway.PainHPV+ head and neck cancer-derived small extracellular vesicles communicate with TRPV1+ neurons to mediate cancer pain.PMC10915104R01DE032712R01 NS121259R01 DE032712R01NS1212592020Folger JKHeussner MPetroff MReimers MVermeer PDTykocki NEvans CMInyang KELaumet GfalseHPV+ head and neck cancer-derived small extracellular vesicles communicate with TRPV1+ neurons to mediate cancer pain.<h4>Abstract</h4>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. Although recent works have shed some light of the biology underlying pain in HPV-negative oral cancers, the mechanisms mediating pain in HPV+ cancers remain unknown. 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 naive mice that is prevented by QX-314 treatment and in Trpv1-/- mice. Cancer-sEVs triggered calcium influx in nociceptors, and inhibition or ablation of nociceptors protects 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. In summary, our work reveals that HPV+ head and neck squamous cell carcinoma-derived sEVs alter TRPV1+ neurons by promoting nascent translation to mediate cancer pain and identified several promising therapeutic targets to interfere with this pathway.2024-01-01T00:00:00Z2024 Mar2026-06-01T11:13:40.338Z2025-06-26T03:06:04.661ZS-EPMC109151043767856610.1097/j.pain.0000000000003045