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

Abstract

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 naive 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.

Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer

“…Thus, significantly elevated expression of Fus by ipsilateral TGM neurons from tumor-bearing animals suggests the presence of neuronal injury induced by the malignancy. This is consistent with our previous findings 54 and those of others 55 showing that tumorinfiltrating nerves harbor higher expression of nerve-injury transcripts and neuronal sensitization.…”