CNSC-18. SENSORY NEURON ACTIVITY PROMOTES TUMOR PROGRESSION IN MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (MPNST) VIA TRPV1⁺ NOCICEPTOR SIGNALING

Abstract BACKGROUND Neural infiltration is a hallmark of malignancy and correlates with poor clinical outcomes in several cancers. Neuronal activity is emerging as a driver of cancer progression and pain, raising interests in nociceptors as potential therapeutic targets. Several cancers cause intractable pain and are innervated by sensory neurons, suggesting that nociceptor activity may both mediate pain and promote tumor progression. We used MPNST as a model to investigate how sensory neuron activity contributes to tumor growth. METHODS In vivo models were generated by engrafting mouse MPNST cells into the sciatic nerve of mice, followed by pain behavioral assays and tumor growth measurements. We selectively stimulated Aβ, Aδ, and C fibers to assess sensory neuron subtype-dependent effects on tumor progression. The transient receptor potential vanilloid 1 channel (TRPV1) antagonist, AMG9810, was used in vitro and in vivo to test the role of TRPV1⁺ nociceptors in tumor growth. Primary dorsal root ganglion (DRG) sensory neuron cultures were prepared for multielectrode array recordings, calcium imaging and co-culture with MPNST cells. RESULTS MPNST-bearing mice exhibited hypersensitivity to mechanical and thermal pain stimuli and exhibited ongoing pain. MPNST-conditioned media increased sensory neuron activity, intracellular calcium concentration, and ATF3 expression in DRG neurons. Selective stimulation of C fibers, but not Aβ or Aδ fibers, enhanced tumor growth, which was blocked by AMG9810. Conditioned media from activated TRPV1⁺ DRG neurons increased MPNST cell growth in vitro, suggesting a role of neuronal activity-dependent paracrine factors in driving tumor cell growth. CONCLUSIONS MPNST is a painful and aggressive cancer originating in the peripheral nerves. Our findings reveal a feedforward loop that MPNST cells increase TRPV1⁺ nociceptor activity, which further promotes tumor progression. Targeting nociceptors may offer a dual therapeutic benefit by alleviating cancer pain and limiting MPNST growth.