Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and has a dismal 50% survival rate. Treatment for HNSCC is expensive and aggressive; surviving patients are left with significant physical impairment and emotional burden. Despite limited therapeutic options and poor survival, no novel effective therapy has been developed in 50 years. Perineural invasion (PNI) is a prognostic factor of poor survival in multiple cancers, including HNSCC, prostate and pancreatic cancers. If PNI is detected in HNSCC, the survival rate drops to 20%. Despite this alarming statistic, PNI is one of the least studied cancer phenotypes. Long-thought to be a passive process, new evidence demonstrates that PNI is an active process where tumor cells must degrade multiple layers of perineural sheath to spread. PNI leads to sensory disturbances including numbness, formication and cancer-associated pain. The nerve-tumor crosstalk necessary to promote PNI is understudied due to the lack of appropriate models that allow observation of nerve-tumor interactions. Due to this deficit in investigations no anti-PNI therapies are available. In this study, we present a novel in vivo model of PNI to characterize interactions between nerves and tumors. This model uses the chicken chorioallantoic membrane in vivo platform with a grafted human HNSCC cell line adjacent to an implanted rat dorsal root ganglion. Mechanistic studies indicate that the neuropeptide galanin (GAL) mediates nerve-tumor crosstalk via activation of galanin receptor 2 (GALR2), a G-protein coupled receptor. Nerves initiate PNI via release of GAL, which induces GALR2 on cancer cells. Through a novel signaling mechanism of tumor progression, activated GALR2 induces nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NFATc2)-mediated transcription of GAL and cyclooxygenase-2 (COX2) in cancer. Prostaglandin E2, a conversion product of COX2, promotes invasion of cancer cells and in a feedback loop, GAL promotes tumor neuritogenesis. Clinical data show that expression of proteins involved in this cascade are correlated with poor survival. Importantly, the GALR2 inhibitor M871 blocks PNI in the CAM in vivo model. This study provides evidence of the dynamic interaction between nerve and cancer cells that facilitates PNI
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