Stromal control of sympathetic rewiring in metastatic lymph nodes

Abstract

Metastatic lymph nodes (LNs) are dynamically remodeled tissues, but this process has been understood mainly in immune and stromal terms. We show that tumor-driven LN remodeling also involves adaptive neural rewiring. In a mouse model of nodal metastasis, sympathetic fibers, but not sensory fibers, progressively expanded during LN remodeling and tracked with metastatic progression. Fibroblastic reticular cells (FRCs) adopted a neuro-supportive program characterized by increased hepatocyte growth factor (HGF) production, while local stromal HGF acted through MET on sympathetic neurons to stimulate neurite outgrowth. Increased substrate stiffness enhanced FRC activation and HGF production, suggesting that mechanical remodeling may reinforce the neuro-supportive stromal state. Inhibition of HGF signaling or ablation of sympathetic innervation reduced LN enlargement and nodal tumor burden. These findings identify neural plasticity as a functional component of the metastatic LN niche and reveal a stromal/mechanical/neural framework that supports metastatic LN progression.

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BibTeX RIS

BibTeX

@misc{li2026stromal,
  title = {{Stromal control of sympathetic rewiring in metastatic lymph nodes}},
  author = {J. Li and X. Zhang and G.-H. Su and L. Hu and Q. Li and H. Li and R. Lu and T.-H. Wei and W.-J. Huang and Y.-Q. Zhou and J.-X. Xie and Y.-Y. Wang and T.-S. Bao and F. Wang and Y.-K. Li and S. Zhang and C.-J. Xu and J. Song and S.-Q. Yi and M.-J. Xu and X.-W. Li and S. Jiang and J. Xu and X.-L. Zhang and D.-X. Li and Z. Zhang},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.21.760843},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.21.760843v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Stromal control of sympathetic rewiring in metastatic lymph nodes
AU  - J. Li
AU  - X. Zhang
AU  - G.-H. Su
AU  - L. Hu
AU  - Q. Li
AU  - H. Li
AU  - R. Lu
AU  - T.-H. Wei
AU  - W.-J. Huang
AU  - Y.-Q. Zhou
AU  - J.-X. Xie
AU  - Y.-Y. Wang
AU  - T.-S. Bao
AU  - F. Wang
AU  - Y.-K. Li
AU  - S. Zhang
AU  - C.-J. Xu
AU  - J. Song
AU  - S.-Q. Yi
AU  - M.-J. Xu
AU  - X.-W. Li
AU  - S. Jiang
AU  - J. Xu
AU  - X.-L. Zhang
AU  - D.-X. Li
AU  - Z. Zhang
PY  - 2026
DA  - 2026/10/21
PB  - bioRxiv
DO  - 10.64898/2026.10.21.760843
UR  - https://www.biorxiv.org/content/10.64898/2026.10.21.760843v1
AB  - Metastatic lymph nodes (LNs) are dynamically remodeled tissues, but this process has been understood mainly in immune and stromal terms. We show that tumor-driven LN remodeling also involves adaptive neural rewiring. In a mouse model of nodal metastasis, sympathetic fibers, but not sensory fibers, progressively expanded during LN remodeling and tracked with metastatic progression. Fibroblastic reticular cells (FRCs) adopted a neuro-supportive program characterized by increased hepatocyte growth factor (HGF) production, while local stromal HGF acted through MET on sympathetic neurons to stimulate neurite outgrowth. Increased substrate stiffness enhanced FRC activation and HGF production, suggesting that mechanical remodeling may reinforce the neuro-supportive stromal state. Inhibition of HGF signaling or ablation of sympathetic innervation reduced LN enlargement and nodal tumor burden. These findings identify neural plasticity as a functional component of the metastatic LN niche and reveal a stromal/mechanical/neural framework that supports metastatic LN progression.
ER  -

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