2. Academic Validation
  3. Nociceptive neurons promote gastric tumour progression via a CGRP-RAMP1 axis

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

  • Nature. 2025 Apr;640(8059):802-810. doi: 10.1038/s41586-025-08591-1.
Xiaofei Zhi 1 2,  Feijing Wu 1,  Jin Qian 1,  Yosuke Ochiai 1,  Guodong Lian 1,  Ermanno Malagola 1,  Biyun Zheng 1 3,  Ruhong Tu 1,  Yi Zeng 1,  Hiroki Kobayashi 1,  Zhangchuan Xia 4,  Ruizhi Wang 5 6,  Yueqing Peng 5 6,  Qiongyu Shi 1,  Duan Chen 7,  Sandra W Ryeom 8,  Timothy C Wang 9
Affiliations

Affiliations

  • 1 Division of Digestive and Liver Diseases, Irving Cancer Research Center, Columbia University Medical Center, New York, NY, USA.
  • 2 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China.
  • 3 Department of Gastroenterology, Fujian Medical University Union Hospital, Fujian, China.
  • 4 Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • 5 Institute for Genomic Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • 6 Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • 7 Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
  • 8 Division of Surgical Science, Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA.
  • 9 Division of Digestive and Liver Diseases, Irving Cancer Research Center, Columbia University Medical Center, New York, NY, USA. tcw21@cumc.columbia.edu.
PMID: 39972142 DOI: 10.1038/s41586-025-08591-1
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.

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