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 2

Newly formed sympathetic innervation of 4T1 tumors connects to the brain.

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Newly formed sympathetic innervation of 4T1 tumors connects to the brain...
(A) Schematic diagram of immunofluorescence staining for TH and NF-L in breast tumors (n = 4 for each group). (B) Representative images showing immunofluorescence staining for TH and NF-L at days 5, 7, and 9 after 4T1 cell inoculation. Scale bars: 100 μm. (C) Quantification of TH+ sympathetic nerve fibers in outer regions of the tumor (field surface = 0.15 mm2; n = 4 for each group). (D) Experimental scheme showing the transplantation of 4T1 cells and intratumoral injection of the neurotropic retrograde transpolysynaptic pseudorabies virus PRV-EGFP. (E–J) Representative images showing PRV-infected neurons (green) in the intermediolateral cell column (IML) (E) and CeM (F–J) from the mice 6 days after PRV-EGFP injection into the tumor tissue. Scale bars: 200 μm. (K) Quantification of PRV+ neurons in the left and right CeM (n = 5). (L) Representative images and quantification of PRV+CRH+ neurons among PRV+ neurons in the CeM (n = 5). (M) Representative images and quantification of PRV+TH+ neurons among PRV+ neurons in the LPGi (n = 5). Scale bars: 20 μm (L and M). Data are presented as the mean ± SEM, except in box and half violin plots (L and M), 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 1-way ANOVA followed by Tukey post hoc test (C) and 2-tailed, unpaired Student’s t test (K). BLA, basolateral amygdaloid nucleus; CeL, central nucleus of the amygdala, lateral division; DH, dorsal horn; VH, ventral horn.