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 system1,2,3. 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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Data availability
The sequencing data reported in this paper are available at the GEO under accession number GSE243578. The single-cell publicly available data used in this study are available in the GEO (GSE157694 and GSE116514) and OMIX (OMIX001073) databases. Data from the TCGA study are publicly available online (https://portal.gdc.cancer.gov). Source data are provided with this paper.
Code availability
No newly generated codes were used in this paper.
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Acknowledgements
This work was supported by grants UO1DK103155, R01DK128195, R01CA272901, R01CA224428 and W81XWH-21-10901 as well as an NCI Outstanding Investigator Award (R35CA210088) to T.C.W. S.W.R. is supported by grants R01CA272891 and P50CA127003. This research was supported in part through the NIH/NCI Cancer Center Support Grant P30CA013696 and used the resources of the Herbert Irving Comprehensive Cancer Center Flow Cytometry Shared Resources, Molecular Pathology (MPSR), Genomics and High Throughput Screening, the Oncology Precision Therapeutics and Imaging Core (OPTIC) and the Genetically Modified Mouse Model Shared Resource (GMMMSR). This research was also supported by the Columbia University Digestive and Liver Disease Research Center (CU-DLDRC) P30DK132710 grant and its Bio-Imaging, Organoid and Bioinformatics/Single-Cell Analysis Cores. We thank the core directors, managers and staff for their expert assistance with our studies; the staff at Tonix Pharmaceuticals and the Torrey Coast Foundation for support; the members of the Core facilities, especially the Animal Facility at the Institute of Comparative Medicine at Columbia University for support; and the members of the Wang and Ryeom laboratories for input throughout the course of this study.
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X.Z. and T.C.W. conceived, designed the study and wrote the manuscript. X.Z., F.W., J.Q., Y.O., G.L., B.Z., R.T., Y.Z., H.K. and Q.S. performed the in vivo experiments. E.M. performed the computational analyses of single-cell RNA-seq data. R.W. and Y.P. performed electrophysiology experiments. Z.X. performed western blotting experiments. S.W.R. generated and characterized Tcon mice and ACKP cells. E.M., Y.P., D.C. and S.W.R. participated in the discussion. T.C.W. generated the concepts, analysed and interpretated the data, developed the idea and hypothesis, and secured the funding.
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Extended data figures and tables
Extended Data Fig. 1 Neural expansion in GCs.
Representative images of (a) sensory (CGRP), (b) sympathetic (TH) and parasympathetic (VAChT) nerves in mouse gastric cancers (n = 5 mice/group). Scale bar, 100 μm. (c) Representative images and quantification of CGRP+, NF200+, Piezo2+, TH+, and VAChT+ nerves in mouse orthotopic and subcutaneous tumours (n = 6 mice/group). Scale bar, 100 μm. (d) Distribution of CGRP+ nerves in GCs (n = 5 mice/group). Data represent mean ± SEM, and P values were calculated by ANOVA in c. The statistical tests were two-sided.
Extended Data Fig. 2 Gastric epithelial injure upregulated Ngf expression.
(a) Representative images of HE staining in mouse stomach treated with vehicle or DMP-777, and Ngf expression in epithelial cells (n = 5 mice/group). Scale bar, 100 μm. (b) Representative images of HE staining in mouse stomach treated with vehicle or high dose of MNU, and Ngf expression in epithelial cells (n = 5 mice/group). Scale bar, 100 μm. (c) Relative expression of Ngf in non-mutant (GFP−) and Kras-mutant (GFP+) gastric epithelial cells (n = 3 mice/group). Mist1+ Kras-mutant gastric epithelial cells were isolated from Mist1-CreERT; KrasG12D; tGFP mice after tamoxifen induction 1 month. (d) Relative expression of Ngf in total epithelial cells, YFP- epithelial cells and YFP+ malignant cells from Atp4b-Cre; Cdh1fl/fl; KrasG12D; Trp53 fl/fl; YFP mice (n = 5 mice/group). (e) Representative images of Ngf in situ hybridization in mouse GCs (n = 5 mice/group). Scale bar, 100 μm. (f) Representative images and (g) quantification of sensory nerves and micro vessels in NGF-overexpression mice and control mice (n = 5 mice/group). Scale bar, 100 μm. (h) Representative images of sensory nerves in mouse gastric cancers treated by Entrectinib or Vehicle (n = 5 mice/group). Scale bar, 100 μm. Data represent mean ± SEM, and P values were calculated by ANOVA in a, b and d, by t test in c and g. The statistical tests were two-sided.
Extended Data Fig. 3 Nociceptive neurons in ganglia.
(a) Size distribution of tracer-positive neurons. (b) Representative images and quantification of CGRP+ neurons and IB4+ neurons in ganglia (n = 3 mice). Scale bar, 100 μm. (c) Representative images and quantification of CGRP+, SP+, SST+ neurons in ganglia (n = 3 mice). Scale bar, 100 μm. SP, Substance P. SST, Somatostatin. (d) Representative images and (e) quantification of neural tracing in NGF-overexpression mouse (n = 4 mice/group). Scale bar, 100 μm. (f) Quantification of molecular subtypes of the stomach-innervating sensory neurons in NGF-overexpression mouse (n = 4 mice/group). (g) Representative images of neural tracing in RTX-treated mice (n = 3 mice). Scale bar, 100 μm. (h) Relative expression of TrkA in sympathetic, parasympathetic and GC-traced sensory neurons (n = 5 mice). Data represent mean ± SEM, and P values were calculated by t test in e, by ANOVA in h. The statistical tests were two-sided.
Extended Data Fig. 4 CGRP/Ramp1 expression in GCs.
(a) Expression levels of Calca in the stomach-innervating sensory neurons from the NGF-overexpression mice and the control mice (n = 10 mice/group). (b) Concentrations of CGRP peptide in the stomach from the NGF-overexpression mice and the control mice (n = 10 mice/group). (c) Dot plot of single-cell transcriptome data of Substance P receptors and Somatostatin receptors from mouse stomach (GSE157694 and GSE116514) and human stomach (OMIX001073). (d) UMAP of single-cell transcriptome data from mouse stomach (GSE157694). (e) Representative image of in situ hybridization of Ramp1 RNA in mouse gastric antrum (n = 5 mice/group). Scale bar, 100 μm. (f) Representative images and (g) quantification of in situ hybridization (RNAscope) of Calcrl RNA in mouse stomach and gastric cancers (n = 5 mice/group). Scale bar, 100 μm. (h) RNA levels of Ramp1 and Calcrl in YFP+ cell from Atp4b-Cre; Cdh1fl/fl; KrasG12D; Trp53fl/fl; YFP mice (n = 3 mice/group). (i) protein levels of Ramp1 and Calcrl in mouse GC cell (ACKP) and human GC cells (KATO III and AGC). (j-k) Kaplan-Meier curves of TCGA survival data. Data represent mean ± SEM, and P values were calculated by t test in a, b and g, by Logrank in j and k. The statistical tests were two-sided.
Extended Data Fig. 5 Nociceptive neurons enhanced gastric ulcer regeneration and gastric cancer growth.
(a) Representative images of gastric ulcer samples and Ki-67 staining (n = 5 mice/group). Scale bar, 100 μm. Quantification of (b) ulcer area and (c) Ki-67 staining. (d) Representative MRI images from orthotopic GC model. (e) Representative images and (f) quantification of DT-induced nociceptive neuron ablation (n = 5 mice/group). Scale bar, 100 μm. (g) Representative images and (h) quantification of CGRP+ nerves in GCs from DT-treated mice (n = 10 mice/group). Scale bar, 100 μm. (i) Concentrations of CGRP peptide in GCs from DT-treated mice (n = 10 mice/group). (j) Representative images and (k) quantification of MNU-induced GCs from nociceptive neuron-ablated mice or control mice (n = 10 mice/group). (l) Representative images and (m) quantification of syngeneic orthotopic tumours from nociceptive neuron-ablated mice or control mice (n = 10 mice/group). (n) Representative images and (o) quantification of syngeneic orthotopic tumours from nociceptive neuron-ablated mice treated with vehicle or Rimegepant (n = 10 mice/group). (p) Representative images and (q) quantification of co-staining of mCherry and CGRP (n = 10 mice/group). Scale bar, 100 μm. (r) Representative images and (s) quantification of syngeneic orthotopic tumours from Calca-Cre mice with injection of AAV-hSyn-DIO-hM3Dq-mCherry (n = 10 mice/group). (t) Representative images and (u) quantification of syngeneic orthotopic tumours from C21-activated mice (n = 10 mice/group). Data represent mean ± SEM, and P values were calculated by t test in b, c, f, h, i, k, m, o, q, s and u. The statistical tests were two-sided.
Extended Data Fig. 6 CGRP promoted the proliferation of gastric cancer spheroids.
(a) Representative images and (b) quantification of gastric cancer spheroids treated by CGRP or Rimegepant (n = 60 spheroids/group). Scale bar, 100 μm. (c) Representative images and (d) quantification of Edu staining in (a) (n = 20 spheroids/group). Scale bar, 100 μm. (e) Proliferation curve of ACKP cells (n = 3 experiments/group). Data represent mean ± SEM, and P values were calculated by ANOVA in b and d. The statistical tests were two-sided.
Extended Data Fig. 7 Nociceptive neurons regulated the number and function of gastric CAFs.
(a) Representative images and (b) quantification of Pdgfra+ CAFs in orthotopic tumours (n = 5 mice/group). Scale bar, 100 μm. (c) Flow chart of gastric CAFs isolation. (d) Proliferation curve of gastric CAFs (n = 3 mice/group). (e) Expression levels of CAF-associated cytokines in gastric CAFs treated with vehicle of CGRP (n = 3 mice/group). Data represent mean ± SEM, and P values were calculated by t test in b and e. The statistical tests were two-sided.
Extended Data Fig. 8 Nociceptive neurons promote GC metastasis in a spontaneous metastasis model.
(a) The spontaneous metastatic model was done by resecting the primary tumour followed by an esophagojejunostomy with Roux-en-Y anastomosis. (b) Mice were monitored weekly with bioluminescence (IVIS) following resection of the primary tumour. Liver metastases were detectable from the third week. (c) Representative images and (d) quantification of Ki-67 staining in liver metastasis (n = 6 lesions/group). Scale bar, 100 μm. (e) Representative images and (f) quantification of sensory nerves (red) in liver metastatic area (yellow) and adjacent area (n = 5 lesions/group). Scale bar, 100 μm. (g) Representative images of sensory nerves in normal and metastatic lymph nodes. Scale bar, 100 μm. (h) Representative images and (i) quantification of α-SMA staining in liver metastasis (n = 5 lesions/group). Scale bar, 100 μm. (j) UMAP of single-cell transcriptome data from mouse liver (GSE174748). Data represent mean ± SEM, and P values were calculated by t test in d, f and i. The statistical tests were two-sided.
Extended Data Fig. 9 Interaction between nociceptive neurons and GC.
(a) Co-staining of tdTomato and TUBB3 in DRGs from Trpv1-Cre; tdTomato mice. Scale bar, 100 μm. (b) Representative current traces in ChR2-expressing ACKP cell (ChR2+) and non-ChR2 ACKP cell (ChR2−). The waveforms of currents were obtained by depolarizing the membrane with 4 s test pluses from −125 to +100 mV at 25 mV steps (9 sweeps, 5 s interval). The 473 nm laser was delivered to clamped cells for 2 s (blue). (c) Current-voltage relationships (I-V) in ChR2+ (n = 14) and ChR2− (n = 15) cells. The currents (pA) of each cell were normalized by dividing to its cell capacitance (pF). (d) Representative traces of neurons recorded in Fig. 5d responding to GC cells. (e) Representative images and (f) quantification of coculture of DRG (from Trpv1-Cre; tdTomato mice) and GC spheroids (with Ngf-knockout ACKP cells) (n = 5 experiments/group). Scale bar, 100 μm. Representative images of in situ hybridization (RNAscope) of Ngf in Cck2r+ organoids (g) and Ramp1-knockout GC spheroids (h). Scale bar, 100 μm. (i) Coculture of DRG (from Trpv1-Cre; hM3Dq; tdTomato mouse) and Ramp1-knockout GC spheroids (infected with rAAV-CMV-jRGECO1a), nociceptive neurons were treated with CNO and calcium indicator jRGECO1a (red) in GC spheroids was monitored (n = 3 experiments). Scale bar, 100 μm. (j) Coculture of Botox-treated DRG (from Trpv1-Cre; hM3Dq; tdTomato mouse) and GC spheroids (infected with rAAV-CMV-jRGECO1a), nociceptive neurons were treated with CNO and calcium indicator jRGECO1a (red) in GC spheroids was monitored (n = 3 experiments). Scale bar, 100 μm. (k-l) GC spheroids proliferation was detected with CellTiter-Glo 3D cell viability assay (n = 5 experiments/group). Data represent mean ± SEM, and P values were calculated by t test in f, and by ANOVA in k and l. The statistical tests were two-sided.
Extended Data Fig. 10 Nociceptive neurons activate Rb/E2F signalling depending on CaMK and PI3K.
(a) Neuron-connected spheroids and unconnected spheroids were split. Expression levels of chemical synaptic genes, electrical synaptic genes and neurodevelopmental genes were analysed (n = 3 experiments). (b) Concentrations of CGRP peptide in orthotopic ACKP-ChR2 tumours from Trpv1-Cre; GCamp6s; tdTomato mice (n = 3 mice/group). (c) PCA plot of bulk RNA sequencing data from cancer spheroids alone, cancer spheroids cocultured with DRG, and cancer spheroids cocultured with CNO-activated DRG (n = 3 experiments/group). (d) GSEA plot of top 20 enhanced pathways in each comparison. (e) Heat map of proliferation genes, Rb-E2F signal enhancer genes and Rb-E2F signal repressor genes. (f) Relative E2F activity in ACKP cells treated with CGRP or kinase inhibitors. Wortmannin, PI3K inhibitor (n = 3 experiments/group). KN-93, CaMK inhibitor. ASN007, ERK inhibitor. ST034307, PKA inhibitor. (g) Representative images and (h) quantification of p-Rb staining in orthotopic tumours from CNO-treated mice (n = 5 mice/group). Scale bar, 100 μm. (i) Representative images and correlation test of sensory nerve and p-Rb staining in human GC tissue microarray (n = 50 cases). Scale bar, 100 μm. (j) Graphical abstract: Gastric cancer is innervated by nociceptive neurons from ipsilateral jugular nucleus complex and dorsal root ganglia (T7-T13). Gastric cancer cells increase the expression of NGF which attracts the expansion of nociceptive nerves. NGF binds to TrkA receptor causing CGRP synthesis and release from nociceptive nerves. In turn, CGRP activates Calcrl/Ramp1 receptor and promotes E2F activity through PI3K signalling and CaMK signalling in gastric cancer cells. Data represent mean ± SEM, and P values were calculated by ANOVA in f, by t test in b and h, and by spearman’s rank correlation test in i. The statistical tests were two-sided. The diagram in j was created using BioRender.
Supplementary information
Supplementary Figures
Supplementary Figs. 1–4.
Supplementary Video 1
In vivo calcium imaging in the jugular nucleus complex. In vivo calcium imaging was done with Trpv1-cre;GCaMP6s;tdTomato mice. GCaMP6s fluorescence (green) was continuously recorded at 488 nm excitation/510–550 nm emission.
Supplementary Video 2
The connections between nociceptive neurons and GC spheroids. DRGs (from Trpv1-cre;hM3Dq;tdTomato mice) were cocultured with GC spheroids (from Atp4b-cre;Cdh1fl/fl;KrasG12D;Trp53 fl/fl;YFP mice). The connections between nociceptive neurons (red) and GC spheroids (yellow) are shown as a 3D confocal video.
Supplementary Video 3
Coculture DRGs with normal gastric organoid. DRGs (from Trpv1-cre;tdTomato mice) were cocultured with normal gastric organoids (from Cck2r-creERT;ZsGreen mice). Nociceptive neurons (red) and normal gastric organoid (green) are shown as a 3D confocal video.
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Zhi, X., Wu, F., Qian, J. et al. Nociceptive neurons promote gastric tumour progression via a CGRP–RAMP1 axis. Nature 640, 802–810 (2025). https://doi.org/10.1038/s41586-025-08591-1
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DOI: https://doi.org/10.1038/s41586-025-08591-1
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