Nociceptive neurons promote gastric tumour progression via a CGRP-RAMP1 axis.

Abstract

Cancer cells have been shown to exploit neurons to modulate their survival and growth, including through the establishment of neural circuits within the central nervous system^1-3. Here we report a distinct pattern of cancer-nerve interactions between the peripheral nervous system and gastric cancer. In multiple mouse models of gastric cancer, nociceptive nerves demonstrated the greatest degree of nerve expansion in an NGF-dependent manner. Neural tracing identified CGRP⁺ peptidergic neurons as the primary gastric sensory neurons. Three-dimensional co-culture models showed that sensory neurons directly connect with gastric cancer spheroids. Chemogenetic activation of sensory neurons induced the release of calcium into the cytoplasm of cancer cells, promoting tumour growth and metastasis. Pharmacological ablation of sensory neurons or treatment with CGRP inhibitors suppressed tumour growth and extended survival. Depolarization of gastric tumour membranes through in vivo optogenetic activation led to enhanced calcium flux in jugular nucleus complex and CGRP release, defining a cancer cell-peptidergic neuronal circuit. Together, these findings establish the functional connectivity between cancer and sensory neurons, identifying this pathway as a potential therapeutic target.