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 7

Optogenetic stimulation of the CeMCRH→LPGi circuit activates sympathetic nerves in 4T1 tumors.

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Optogenetic stimulation of the CeMCRH→LPGi circuit activates sympathetic...
(A) Schematic of the Cre-dependent retrograde transmonosynaptic rabies virus–tracing strategy in WT BALB/c mice. (B) EGFP-labeled neurons in the CeM traced from LPGiCA neurons. Scale bar: 200 μm. (C and D) Representative images showing colocalization of EGFP with CRH in the CeM (C) and summarized data (D; n = 5). Scale bar: 200 μm. (E and F) Timeline and scheme for recording the activities of sympathetic nerves distributed in the tumor stroma during optogenetic stimulation of the CeMCRH→LPGi circuit in the CeM. (G and H) Typical image of viruses (AAV and pLenti) expression in the CeM (G) and tumor stroma (H). Scale bars: 200 um (G) and 20 um (H). (I and J) Comparison of the mean ΔF/F (0–5 s) (I) and peak amplitude of ΔF/F (J) between the GRABNE2h and EGFP groups (n = 6 for each group). (K) Average fluorescence change in the GRABNE2h and EGFP groups, with shaded areas indicating the SEM. (L and M) Heatmaps show the average fluorescence change in the GRABNE2h (L) and EGFP (M) groups. Data are presented as the mean ± SEM, except in box and half violin plots (D), in which center lines indicate the median, box edges represent the first and third quartiles, and whiskers denote minimal and maximal values. ***P < 0.001, by 2-tailed, unpaired Student’s t test (I and J).