Nociceptive neurons promote gastric tumour progression via a CGRP–RAMP1 axis

Xiaofei Zhi, Feijing Wu, Jin Qian, Yosuke Ochiai, Guodong Lian, Ermanno Malagola, Biyun Zheng, Ruhong Tu, Yi Zeng, Hiroki Kobayashi, Zhangchuan Xia, Ruizhi Wang, Yueqing Peng, Qiongyu Shi, Duan Chen, Sandra W. Ryeom and Timothy C. Wang ()
Additional contact information
Xiaofei Zhi: Columbia University Medical Center
Feijing Wu: Columbia University Medical Center
Jin Qian: Columbia University Medical Center
Yosuke Ochiai: Columbia University Medical Center
Guodong Lian: Columbia University Medical Center
Ermanno Malagola: Columbia University Medical Center
Biyun Zheng: Columbia University Medical Center
Ruhong Tu: Columbia University Medical Center
Yi Zeng: Columbia University Medical Center
Hiroki Kobayashi: Columbia University Medical Center
Zhangchuan Xia: Columbia University Irving Medical Center
Ruizhi Wang: Columbia University
Yueqing Peng: Columbia University
Qiongyu Shi: Columbia University Medical Center
Duan Chen: Norwegian University of Science and Technology
Sandra W. Ryeom: Columbia University Irving Medical Center
Timothy C. Wang: Columbia University Medical Center

Nature, 2025, vol. 640, issue 8059, 802-810

Abstract: 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 system1–3. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08591-1

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