A brain-tumor neural circuit controls breast cancer progression in mice
Si-Yi Xiong, … , Yi Zhang, Guang-Yan Wu
Si-Yi Xiong, … , Yi Zhang, Guang-Yan Wu
Published October 17, 2023
Citation Information: J Clin Invest. 2023;133(24):e167725. https://doi.org/10.1172/JCI167725.
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Research Article Neuroscience Oncology

A brain-tumor neural circuit controls breast cancer progression in mice

Abstract

Tumor burden, considered a common chronic stressor, can cause widespread anxiety. Evidence suggests that cancer-induced anxiety can promote tumor progression, but the underlying neural mechanism remains unclear. Here, we used neuroscience and cancer tools to investigate how the brain contributes to tumor progression via nerve-tumor crosstalk in a mouse model of breast cancer. We show that tumor-bearing mice exhibited significant anxiety-like behaviors and that corticotropin-releasing hormone (CRH) neurons in the central medial amygdala (CeM) were activated. Moreover, we detected newly formed sympathetic nerves in tumors, which established a polysynaptic connection to the brain. Pharmacogenetic or optogenetic inhibition of CeMCRH neurons and the CeMCRH→lateral paragigantocellular nucleus (LPGi) circuit significantly alleviated anxiety-like behaviors and slowed tumor growth. Conversely, artificial activation of CeMCRH neurons and the CeMCRH→LPGi circuit increased anxiety and tumor growth. Importantly, we found alprazolam, an antianxiety drug, to be a promising agent for slowing tumor progression. Furthermore, we show that manipulation of the CeMCRH→LPGi circuit directly regulated the activity of the intratumoral sympathetic nerves and peripheral nerve–derived norepinephrine, which affected tumor progression by modulating antitumor immunity. Together, these findings reveal a brain-tumor neural circuit that contributes to breast cancer progression and provide therapeutic insights for breast cancer.

Authors

Si-Yi Xiong, Hui-Zhong Wen, Li-Meng Dai, Yun-Xiao Lou, Zhao-Qun Wang, Yi-Lun Yi, Xiao-Jing Yan, Ya-Ran Wu, Wei Sun, Peng-Hui Chen, Si-Zhe Yang, Xiao-Wei Qi, Yi Zhang, Guang-Yan Wu

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Figure 5

Chemogenetic inhibition of CeMCRH neurons significantly attenuates both cancer-induced anxiety and 4T1 tumor progression.

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Chemogenetic inhibition of CeMCRH neurons significantly attenuates both ...
(A) Schematic of the experimental design. (B) Schematic showing bilateral injection of viruses into the CeM. (C) Representative images showing hM4Di-mCherry expression in CeMCRH neurons. Scale bars: 200 μm and 20 μm. (D–M) Representative heatmaps and summary data of the mCherry (n = 15) and hM4Di (n = 14) groups in the LDT (D–F), the OFT (G–I), and the EPM test (J–M). (N) Chemogenetic inhibition of CeMCRH neurons significantly slowed 4T1 tumor growth. (O) Representative tumors dissected from mice of the 2 groups. Scale bar: 10 mm. (P) Chemogenetic inhibition of CeMCRH neurons significantly reduced 4T1 tumor weight. (Q) Representative bioluminescence images of mice of the 2 groups. Scale bar: 20 mm. (R) Chemogenetic inhibition of CeMCRH neurons significantly reduced the luciferase intensity of 4T1 tumors (P and R: mCherry, n = 15, hM4Di, n = 14). (S and T) Chemogenetic inhibition of CeMCRH neurons significantly decreased NE content of 4T1 orthotopic mammary (S) and ectopic (T) tumors (S: mCherry, n = 15, hM4Di, n = 14; T: n = 6 for each group). (U) Timeline for immunofluorescence staining of 4T1 tumor tissues. (V and W) Representative images and quantification of Ki67+ cells (V) and TUNEL+ cells (W) within 4T1 tumors (n = 6 for each group). Scale bars: 50 μm. Data are presented as the mean ± SEM, except in box plots (H, I, S, and T), in which center lines indicate the median, box edges represent the first and third quartiles, and whiskers denote minimal and maximal values. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way, repeated-measures ANOVA followed by separate 1-way ANOVA (N) and 2-tailed, unpaired Student’s t test (E, F, H, I, K–M, P, R–T, V, and W).