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Colorectal cancer cells hijack a brain–gut polysynaptic circuit from the lateral septum to enteric neurons to sustain tumor growth

Nature Cancer (2025)Cite this article

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Abstract

The bidirectional interaction between the brain and peripheral tumors is critical but poorly understood. Here we show GABAergic neurons in the lateral septum, a key brain region implicated in emotional regulation, connect via a polysynaptic circuit to enteric cholinergic neurons that send nerve fibers into the tumor microenvironment, which were then hijacked by colorectal cancer cells to sustain tumor growth in mice. Functionally, activation of this septo-enteric circuit induces GABA release from enteric cholinergic neurons, which in turn activates epsilon-subunit-containing GABAA receptors on tumor cells. Notably, chronic restraint stress potentiates activity within this circuit, exacerbating tumor progression. Clinically, patients with colorectal cancer exhibiting elevated neuronal activity in the septal region present with larger primary tumors. Collectively, our findings uncover a stress-sensitive septo-enteric polysynaptic pathway exploited by cancer cells to promote tumor growth, underscoring the previously unrecognized role of lateral septum-mediated neural circuitry and psychological stress in cancer progression.

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Fig. 1: Retrograde tracing links lateral septum to CRC growth.
Fig. 2: LSGABA neurons polysynaptically regulate tumor-innervating cholinergic neurons.
Fig. 3: Activation of LSGABA neurons promotes CRC growth and inactivation of LSGABA neurons inhibits CRC growth.
Fig. 4: LSGABA–LHGABA circuit promotes colonic motility and rectal tumor growth.
Fig. 5: LSGABA neuron-induced tumor growth requires enteric cholinergic activation.
Fig. 6: Polysynaptic septo-enteric circuit drives CRC growth via GABA.
Fig. 7: Chronic stress activates septo-enteric polysynaptic circuit leading to CRC growth.
Fig. 8: Human septal metabolic activity correlates with CRC progression.

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Data availability

All data supporting the findings of this study are included in the paper and its supplementary files. The raw sequence data from the transcriptome sequencing have been deposited in the Sequence Read Archive at NCBI under BioProject PRJNA904576. Previously published microarray data that were reanalyzed here are available in the Gene Expression Omnibus under accession codes GSE41258 (ref. 34) and GSE71187 (ref. 35). The dataset derived from this resource that supports the findings of this study is available in Guinney et al.36. Source data are provided with this paper.

Code availability

No custom algorithms were used in this study.

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Acknowledgements

We sincerely thank B.-X. Li from Zhongshan School of Medicine, Sun Yat-Sen University, for his valuable technical guidance. This work was supported by grants from the STI2030-Major Projects (2021ZD0202700 to T.-M.G.), National Natural Science Foundation of China (82130080 to J.-M.L., U24A201290 to J.-M.L., 82090032 to T.-M.G. and T2394535 to T.-M.G.), Natural Science Foundation of Jiangxi (20242BAB27004 to J.-M.L.) and Natural Science Foundation of Guangdong (2022A1515010418 to Y.L. and 2024A1515030196 to Y.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Ying Li, Hao Yu, Zi-Ming Li, Kai-Wen Yin, Shi-Yang Jin.

Authors and Affiliations

  1. Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Ying Li, Hao Yu, Kai-Wen Yin, Chao-Chao Chen, Ming-Shi Tan, Chuan-Jie Zhang, Ai-Jun Zhou, En-De Ni, Hui Mo, Chao Qin & Jian-Ming Li

  2. State Key Laboratory of Multi-organ Injury Prevention and Treatment, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Zi-Ming Li, Shi-Yang Jin, Wei-Peng Li, Jian-Ming Yang, Meng-Ling Wang, Jian Hu, Shu-Ji Li & Tian-Ming Gao

  3. Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

    Xun-Hua Liu

  4. Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Xiang Zhang

  5. Department of Pathology, Soochow University Medical School, Suzhou, China

    Jian-Ming Li

  6. The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China

    Jian-Ming Li

  7. Department of Pathology and Institute of Molecular Pathology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China

    Jian-Ming Li

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Contributions

J.-M.L. and T.-M.G. contributed to the conceptualization of the study. J.-M.L., T.-M.G., Y.L. and J.-M.Y. contributed to the study design. Y.L., H.Y., Z.-M.L., K.-W.Y., C.-C.C. and M.-S.T. were involved in data acquisition and analysis for animal and cellular studies. Z.-M.L., S.-Y.J. and W.-P.L. contributed to neuronal interventions and electrophysiological experiments. C.-J.Z. was responsible for acquiring transcriptomic sequencing data from tumors in patients with CRC. X.-H.L., A.-J.Z. and E.-D.N. contributed to the collection of tumor samples and cell proliferation experiments. X.Z., C.-C.C. and Y.L. performed the PET–CT imaging analysis. C.-C.C. and M.-S.T. were involved in the breeding of ChAT-Cre and Ai14 mice. H.M. and C.Q. were responsible for constructing the PDX models. M.-L.W. and J.H. contributed to the breeding of GAD65-Cre mice. S.-J.L. was responsible for instrumental operation. J.-M.L., T.-M.G., Y.L. and H.Y. contributed to data analysis and interpretation. J.-M.L., T.-M.G. and Y.L. were involved in drafting the paper. J.-M.L., T.-M.G. and Y.L. also contributed to securing funding and supervising the study.

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Correspondence to Tian-Ming Gao or Jian-Ming Li.

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Extended data

Extended Data Fig. 1 Tumor innervation predicts poor CRC survival.

(a) Representative images of nerve fibers in human CRC tumors labeled with NF-L/PGP9.5 from 3 patients. (b-e) NF-L+ nerve fibers in 70 CRC patients. (b) Representative images of NF-L+ nerve fibers in tumor sections. (c) Negative correlation with overall survival. (d, e) Higher density/count of NF-L+ nerve fibers predict poorer survival. (f-i) Representative images of NF-L+ nerve fibers in xenograft models. (f) CMT93 rectal CDX (male, C57BL/6 J, n = 16 mice). (g) Sciatic nerve CDX (male, C57BL/6 J, n = 3 mice). (h) SW480 rectal CDX (male, nude, n = 12 mice). (i) PDX (male, B-NDG, n = 3 mice): No NF-L+ nerve fibers. (j) Comparable Ngf/Gabbr1 mRNA in CMT93 cells (n = 3 biological replicates). (k) GW441756 treatment in CMT93 rectal CDX model. NF-L+ nerve fibers in rectal tumors and tumor volome at days 6/10/14 post-injection of cells. At day 6, n = 4 mice per group. At day 10, n = 5 mice per group. At day 14, n = 4 mice per group. The number of NF-L+ nerve fibers is the normalized number in the tumor area of 1 ×108 μm2. The red arrowheads indicate nerve fibers. Data are presented as mean ± SEM. Two-tailed Pearson Correlation Analysis (c), two-tailed Gehan-Breslow-Wilcoxon test (d, e), two-tailed Mann Whitney test (j, nerve density at days 10/14 in k), two-tailed unpaired student’s t test (nerve density at day 6 in k, tumor volume at days 6/10 in k), and two-tailed unpaired student’s t test with Welch’s correction (tumor volume at day 14 in k) are used. n.s., not significant.

Source data

Extended Data Fig. 2 Characterization of LS-enteric neural circuits physiologically.

(a) PRV-mRFP injected into male CMT93 rectal tumors. Co-localization with Th + /CGRP+ /ChAT+ nerve fibers assessed at 84 hours post-injection. n = 3 mice. (b) PRV-mRFP tracing in female CMT93 rectal tumors. mRFP+ cells detected in rectum, spinal cord, LH, and LS at one-week post-injection. n = 3 mice. (c) HSV-eGFP anterograde tracing from LS of male C57BL/6 J mice. Co-localization with nNOS + /VIP + /Th + /CGRP+ nerve fibers in tumors assessed at 48 hours post-injection. n = 3 mice. (d-e) Physiological circuit mapping. (d) PRV-mRFP retrograde tracing from rectum of male C57BL/6 J mice. mRFP+ neurons in rectum and LS assessed at one-week post-injection. n = 3 mice. (e) HSV-eGFP anterograde tracing from LS of male C57BL/6 J mice. eGFP+ neurons in LS and rectum assessed at 30 hours post-injection. n = 3 mice. The white arrowheads indicate the co-labeled nerve fibers. Data are presented as mean ± SEM.

Source data

Extended Data Fig. 3 LS regulates enteric cholinergic neurons by a polysynaptic circuit.

(a) AAV/Retro-DIO-mCherry virus was injected into the rectal tumor of male ChAT-Cre mice, and mCherry+ neurons were detected. n = 3 mice. (b) GAD67-Cre, AAV-DIO-eGFP-TK, and HSV-ΔTK-LSL-tdTomato viruses were injected into the LS of C57BL/6 J mice. Rectal slices were subsequently analyzed. n = 3 mice. (c) The AAV/Retro-DIO-mCherry virus was injected into the rectum of male ChAT-Cre mice, and mCherry+ neurons were detected. n = 3 mice. (d) ChAT-Cre, AAV-DIO-eGFP-TK, and HSV-ΔTK-LSL-tdTomato viruses were injected into the SPN and then tdTomato+ cells were analyzed. n = 3 mice. (e) The PRV-mRFP virus was injected into the rectal tumors of male C57BL/6 J mice, and spinal cord and brain tissues were analyzed at 60-, 84-, 96-, and 108-hours post-injection. n = 2 mice for 60 and 96 hours; n = 3 mice for 84 and 108 hours. The white arrowheads indicate the neurons. Data are presented as mean ± SEM. Illustration of the brain and spinal cord were created in BioRender. Lee, Y. (2025) https://BioRender.com/3qy1oto.

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Extended Data Fig. 4 Chemogenetic inactivation of LSGABA neurons inhibits colorectal tumorigenesis.

(a-b) Viral targeting validation. (a) Co-localization of mCherry+ and GFP+ neurons in LS after AAV-DIO-mCherry injection in GAD67-GFP mice. n = 2 mice. (b) CNO-induced c-Fos’s expression in hM3Dq+ LS neurons (arrowheads; n = 3 mice per group). (c-k) CDX model studies. (c-e) Chemogenetic activation of LSGABA neurons via hM3Dq/CNO. Tumor morphology (c), weight (d), and volume (e). Saline, n = 3 mice; CNO, n = 5 mice. (f-h) Control virus injection in LS. Tumor morphology (f), weight (g), and volume (h). n = 3 mice per group. (i-k) Chemogenetic activation of LSGABA neurons via hM3Dq/DCZ. Tumor morphology (i), weight (j), and volume (k). Control, n = 5 mice; hM3Dq, n = 4 mice. (l-o) Chemogenetic inactivation of LSGABA neurons in male AOM/DSS model. NF-L+ nerve fibers in tumors (l), tumor morphology (m), number (n), and area (o). Red boxes: tumor regions. n = 8 mice per group. (p-t) ApcMin/+ model. (p-q) HSV-eGFP tracing from LS in male ApcMin/+ mice at 24 weeks old. eGFP+ LS neurons (p) and tumor nerve fibers (q) at 48 hours post-injection. n = 3 mice. (r-t) Chemogenetic inactivation of LSGABA neurons in ApcMin/+ model with CNO intraperitoneal injection once every week for 12 times. Tumor morphology (r), number (s), and area (t) in male ApcMin/+ mice at 24 weeks old. n = 7 mice per group. Data are presented as mean ± SEM. Two-tailed unpaired student’s t test (b, g-h, k, n, t), two-tailed unpaired student’s t test with Welch’s correction (d, s), and two-tailed Mann Whitney test (e, j, o) are used. n.s., not significant.

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Extended Data Fig. 5 Inactivation of enteric neurons inhibits colorectal tumor growth.

(a) ChAT+ nerve fibers in SW480 rectal tumors in male Nude mice. n = 3 mice. (b-d) BTXA treatment in male Nude CDX model with injection of SW480 cells. BTXA rectal injections once every week for three cycles. Tumor morphology (b), weight (c), and volume (d). n = 6 mice per group. (e) tdTomato+ cholinergic nerve fibers in sciatic nerve tumors in male ChAT-Cre/Ai14 mice. n = 3 mice. (f-h) Sciatic nerve CDX model with injection of CMT93 cells. BTXA injections in sciatic nerve once every week for three cycles. Tumor morphology (f), weight (g), and volume (h). n = 10 tumors from 5 mice per group. (i) BTXA treatment for 24 hours on CRC cell viability. n = 7 biological replicates per group for SW480 and DLD-1; n = 5 biological replicates per group for MC38 and CMT93. (j-l) Combined chemogenetic activation of LSGABA neurons and BTXA treatment in female C57BL/6 J CDX model with CNO intraperitoneal and BTXA intratumoral injection every four days. Tumor morphology (j), weight (k), and volume (l). n = 5, 6, 6, 6 mice for Control+Saline, hM3Dq+Saline, Control+BTXA, hM3Dq+BTXA respectively. Data are presented as mean ± SEM. Two-tailed Mann Whitney test (c-d, g-h, SW480 cells in i), two-tailed unpaired student’s t test (DLD-1, MC38 and CMT93 cells in i), Ordinary one-way ANOVA with Tukey’s multiple comparisons test (k) or with BKY two-stage FDR correction (l) are used. n.s., not significant.

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Extended Data Fig. 6 GABA signaling mediates neuron-tumor interactions.

(a) Coculture of DRG/enteric neurons with SW480/CMT93-GFP cells. Tuj1+ neurons and GFP+ tumor cells imaged. n = 3 biological replicates. (b) TEM images of CMT93 rectal tumors. n = 12 ultra-thin sections from 3 mice. (c) sEPSCs/sIPSCs in CMT93-GFP/GL261 cells implanted in mPFC. n = 6 cells from 3 mice for each recording. (d) DRG-conditioned medium effects on SW480 (n = 9, 12 biological replicates for Control and DRG medium respectively)/CMT93 (n = 9 biological replicates per group) viability. (e) BTXA-treated DRG-conditioned medium effects on SW480 (n = 9 biological replicates per group)/CMT93 (n = 14 biological replicates per group) viability. (f-i) ACh (f, SW480; g, CMT93; n = 5 biological replicates per group) and glutamate (h, SW480, n = 10 biological replicates for Control, 5 μM, 10 μM, 25 μM, 50 μM and 7 biological replicates for 100 μM; i, CMT93, n = 10 biological replicates for Control, 5 μM, 10 μM, 25 μM, 50 μM and 8 biological replicates for 100 μM) effects on cell viability. (j-k) GABA level in DRG medium (j, n = 6 biological replicates per group)/BTXA-treated DRG medium (k, n = 5 biological replicates per group). (l-p) GABA level in rectal tumors after inhibiting (l, n = 5 mice per group)/activating (m, n = 5, 7 mice for Control and hM3Dq respectively) LSGABA neurons, inhibiting enteric neurons with BTXA (n, C57BL/6 J mice, n = 8, 6 mice for Saline and BTXA respectively; o, Nude mice, n = 6, 5 mice for Saline and BTXA respectively), or chemogenetically modulating enteric cholinergic neurons (p, n = 5, 4, 6 mice for Control, hM4Di and hM3Dq respectively). (q-s) GABA supplement in male C57BL/6 J CDX model. Tumor morphology (q), weight (r), volume (s). n = 5, 6 mice for BTXA+Saline, BTXA + GABA respectively. Green dashed line: tumor margin. (t-v) GABA concentration in ChA-treated DRG medium (t, n = 5 biological replicates per group). ChA (u, n = 6 biological replicates per group) and ChA-treated DRG medium effects on CMT93 viability (v, n = 10, 9 biological replicates for DRG medium, ChA-treated DRG medium respectively). (w-y) ChA treatment in male C57BL/6 J CDX model. Tumor morphology (w), weight (x), volume (y). Vehicle, n = 8 mice; ChA, n = 5 mice. Data are presented as mean ± SEM. Two-tailed unpaired student’s t test (d, SW480 cells in e, j-l, o-p, t, v), two-tailed Mann Whitney test (CMT93 cells in e, m-n, r-s, x-y), and Ordinary one-way ANOVA with Tukey’s multiple comparisons test (f-i, u) are used. n.s., not significant.

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Extended Data Fig. 7 GABRE expression in CRC tumors mediates LSGABA-enteric circuit-driven growth.

(a-b) GABAA (a, n = 6, 6, 5, 5 biological replicates for Control, 5 μM, 10 μM, 25 μM respectively) and GABAB (b, n = 5, 6, 6, 6 biological replicates for Control, 5 μM, 10 μM, 25 μM respectively) receptor agonists effects on SW480 viability. (c-d) GABAA (c, n = 10 biological replicates per group) and GABAB (d, n = 10 biological replicates per group) receptor agonists effects on CMT93 viability. (e-g) BMI treatment in CDX model of male C57BL6/J mice. Tumor morphology (e), weight (f) and volume (g). Vehicle, n = 8 mice; BMI, n = 6 mice. (h-i) Various neurotransmitter receptors expression in CRC vs normal tissues. GSE41258 (h, 54 N/186 T) and GSE71187 (i, 12 N/47 T). (j) Protein levels of GABRE in SW480/CMT93 post-shRNA infection. (k-p) Viability of GABRE-knockdown cells treated with: GABA (k:CMT93, n = 15 biological replicates per group; l:SW480, n = 10, 10, 8 biological replicates for 0 μM, 10 μM and 25 μM respectively in Control cells and 10 biological replicates per group in sh-GABRE), DRG medium (m:CMT93, n = 15 biological replicates per group; n:SW480, n = 9, 10 biological replicates for Control and DRG medium respectively in Control cells and 9 biological replicates per group in sh-GABRE), and enteric neuron medium (o:CMT93, n = 13, 12 biological replicates for Control and ENs medium respectively in Control cells and 13 biological replicates per group in sh-Gabre; p:SW480, n = 10 biological replicates per group). (q-s) Chemogenetic activation of LSGABA neurons in CDX model with the injection of Gabre-knockdown CMT93 cells. Tumor morphology (q), weight (r) and volume (s). n = 6 mice per group. (t) Survival analysis of CRC patients with high or low GABRE expression in tumors across different CMS. n = 82 (low), 82 (high) patients for CMS 1; n = 224 (low), 223 (high) patients for CMS 2; n = 71 (low), 70 (high) patients for CMS 3; n = 132 (low), 132 (high) patients for CMS 4. Data are presented as mean ± SEM. Ordinary one-way ANOVA with Tukey’s multiple comparisons test (a-d, k-p), two-tailed unpaired student’s t test (f-g, r-s), linear models for microarray data with Benjamini-Hochberg method controlling FDR (h-i) and two-tailed Gehan-Breslow-Wilcoxon test (t) are used. n.s., not significant.

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Extended Data Fig. 8 GABA signaling promotes TSPAN1 expression in CRC.

(a-b) Transcriptomic analysis of BMI-treated CMT93 tumors. Numbers of differently expressed genes (a) and mRNA expression of Tspan1 (b). n = 5 mice per group. (c-e) mRNA expression of Tspan1 in Gabre/GABRE knockdown cells treated with: GABA (c:CMT93, n = 6 biological replicates per group; e:SW480, n = 6, 4, 4, 6 biological replicates for Saline+Control, GABA+Control, Saline+sh-GABRE, GABA+sh-GABRE respectively) and DRG neuron medium (d:CMT93, n = 6, 6, 6, 4 biological replicates for Control+Control, DRG medium+Control, Control+sh-Gabre, DRG medium+sh-Gabre respectively). (f-h) GAD65/67 + NF-L+ nerve fibers in 111 CRC patients. Representative images (f) and survival analysis by nerve fiber number (g) and density (h). Low, n = 56 patients; High, n = 55 patients. (i-o) ChAT+ nerve fibers in 81 CRC patients. Representative images (i), survival analysis by nerve fiber number (j) and density (k), correlation analysis of nerve fiber with overall survival (l-m), and tumor volume of patients with low or high nerve fibers (n-o). Low, n = 41 patients; High, n = 40 patients. (p-r) ChAT+ nerve fibers and TSPAN1 expression in 77 CRC patients. Representative images (p) and correlation analysis of ChAT+ nerve fibers and TSPAN1 expression (q-r). The number of ChAT+ nerve fibers was normalized to the tumor area (1 × 108 μm2). Red arrowheads indicate ChAT+ nerve fibers. Data are presented as mean ± SEM. Negative binomial distribution test with Benjamini-Hochberg method controlling FDR (b), Ordinary one-way ANOVA with Tukey’s multiple comparisons test (c) or BKY two-stage FDR correction (d-e), two-tailed Gehan-Breslow-Wilcoxon test (g-h), Log-rank (Mantel-Cox) test (j-k), two-tailed Pearson Correlation Analysis (l-m, q-r), two-tailed unpaired student’s t test (n) and two-tailed unpaired student’s t test with Welch’s correction (o) are used. n.s., not significant.

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Extended Data Fig. 9 GABAergic neurons regulate tumor immunity.

(a) Chemogenetic inhibition of LSGABA neurons in AOM/DSS model. Quantification of tumor-infiltrating immune cells: CD3 + /CD11b + /CD19+ (Control, n = 9 tumors from 4 mice; hM4Di, n = 10 tumors from 5 mice), CD68 + /Ly6C+ (Control, n = 10 tumors from 4 mice; hM4Di, n = 10 tumors from 5 mice). (b) Chemogenetic inactivation of LSGABA neurons in male C57BL/6 J CDX model. Quantification of tumor-infiltrating immune cells: CD3+ (Control, n = 9 mice; hM4Di, n = 5 mice), CD11b + /CD19 + /CD68 + /Ly6C+ (Control, n = 7 mice; hM4Di, n = 5 mice). (c) shGAD67-mediated GAD67 knockdown in ChAT+ neurons in male ChAT-Cre mice. Quantification of tumor-infiltrating immune cells. Scramble, n = 7 mice; shGAD67, n = 4 mice. Data are presented as mean ± SEM. Two-tailed unpaired student’s t test (CD3 + /CD11b + /CD19 + /Ly6C+ in a, CD3 + /CD11b + /CD68 + /Ly6C+ in b, c) and two-tailed unpaired student’s t test with Welch’s correction (CD68+ in a, CD19+ in b) is used. n.s., not significant.

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Extended Data Fig. 10 Stress drives CRC growth via GABRE.

(a-d) CRS-induced neural/immune changes in male C57BL/6 J mice: increased ChAT+ cells in muscular layer (a, n = 5, 6 mice for Control and CRS respectively), elevated Ly6C+ cells in mucosa (b, n = 5, 6 mice for Control and CRS respectively), unchanged ChAT+ cells (c, n = 10, 5 mice for Control and CRS respectively) and Ly6C+ cells (d, n = 7, 5 mice for Control and CRS respectively) in rectal tumors. (e-k) CRS in male C57BL/6 J CDX model with the injection of Gabre knockdown CMT93 cells. Control cells-formed tumors: morphology (f), weight (g), volume (h), n = 8, 6 mice for Control and CRS respectively. Gabre-knockdown cells-formed tumors: morphology (i), weight (j), volume (k), n = 8, 3 mice for Control and CRS respectively. (l-q) CRS-induced neural/immune changes in female C57BL/6 J mice: increased LS c-Fos+ neurons (l, n = 3 mice per group), elevated serum corticosterone (m, n = 8 mice per group) and colorectal GABA (n, n = 8 mice per group), decreased colorectal Ach (o, n = 8 mice per group), increased ChAT+ cells in muscular layer (p, n = 7 mice per group) and unchanged Ly6C+ cells in mucosa (q, n = 8 mice per group). (r-u) Chemogenetic inhibition of LSGABA neurons in female CDX model suffering from CRS (r). Tumor morphology (s), weight (t), volume (u). n = 5, 4, 4, 6 mice for Control+Control, Control+CRS, hM4Di+Control, hM4Di+CRS respectively. Data are presented as mean ± SEM. Two-tailed unpaired student’s t test (a-b, d, g-h, j-l, o-q), two-tailed unpaired student’s t test with Welch’s correction (c), two-tailed Mann Whitney test (m), two-tailed Kolmogorov-Smirnov test (n) and Ordinary one-way ANOVA with Tukey’s multiple comparisons test (t-u) are used. n.s., not significant.

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Li, Y., Yu, H., Li, ZM. et al. Colorectal cancer cells hijack a brain–gut polysynaptic circuit from the lateral septum to enteric neurons to sustain tumor growth. Nat Cancer (2025). https://doi.org/10.1038/s43018-025-01033-x

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