CBNP Seminar

Abstract:

Perineural invasion (PNI), the invasion of peripheral nerves by head and neck squamous cell carcinoma (HNSCC), is associated with poor prognosis and treatment failure. Although PNI is also linked to cancer-associated pain, the mechanisms underlying this pain remain poorly understood. By comparing patient-reported pain phenotypes, we found that PNI is associated with increased pain, particularly mechanically evoked pain during eating, drinking, and talking.

To investigate the neural mechanisms underlying this clinical phenotype, we developed two complementary mouse models of HNSCC-associated PNI. In both models, low-threshold mechanoreceptors became desensitized, whereas high-threshold mechanoreceptors became sensitized, revealing a profound remodeling of peripheral sensory function following tumor–nerve interactions.

To identify potential drivers of these sensory changes, we performed RNA sequencing of human and mouse HNSCC tumors. Cross-species analysis revealed prominent alterations in extracellular matrix (ECM)-related pathways. We therefore investigated how tumor-associated ECM remodeling contributes to neuronal dysfunction and mechanical pain in PNI. We found tumor invasion establishes a spatially restricted perineural mechanical niche in which matrix stiffening engages mechanosensitive signaling to drive neuronal hyperexcitability and mechanical pain.

Together, our findings establish a link between PNI, clinically relevant mechanical pain, sensory neuron remodeling, and tumor ECM alterations, providing new insight into the mechanisms by which tumor–nerve interactions drive pain in HNSCC.