2. Academic Validation
  3. Lymphotoxin-β promotes breast cancer bone metastasis colonization and osteolytic outgrowth

Lymphotoxin-β promotes breast cancer bone metastasis colonization and osteolytic outgrowth

  • Nat Cell Biol. 2024 Aug 15. doi: 10.1038/s41556-024-01478-9.
Xuxiang Wang # 1,  Tengjiang Zhang # 1,  Bingxin Zheng # 2,  Youxue Lu 1,  Yong Liang 1,  Guoyuan Xu 1,  Luyang Zhao 1,  Yuwei Tao 1,  Qianhui Song 1,  Huiwen You 1,  Haitian Hu 1,  Xuan Li 1,  Keyong Sun 1,  Tianqi Li 3,  Zian Zhang 4,  Jianbin Wang 3,  Xun Lan 5,  Deng Pan 5,  Yang-Xin Fu 5,  Bin Yue 6,  Hanqiu Zheng 7 8
Affiliations

Affiliations

  • 1 Center for Cancer Biology, School of Basic Medical Sciences, Tsinghua University, Beijing, China.
  • 2 Department of Orthopedic Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
  • 3 School of Life Sciences and Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China.
  • 4 Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
  • 5 State Key Laboratory of Molecular Oncology and Center for Cancer Biology, School of Basic Medical Sciences, Tsinghua University, Beijing, China.
  • 6 Department of Orthopedic Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China. bonetumoryb@qdu.edu.cn.
  • 7 State Key Laboratory of Molecular Oncology and Center for Cancer Biology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. hanzheng@tsinghua.edu.cn.
  • 8 SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, China. hanzheng@tsinghua.edu.cn.
  • # Contributed equally.
PMID: 39147874 DOI: 10.1038/s41556-024-01478-9
Abstract

Bone metastasis is a lethal consequence of breast Cancer. Here we used single-cell transcriptomics to investigate the molecular mechanisms underlying bone metastasis colonization-the rate-limiting step in the metastatic cascade. We identified that Lymphotoxin-β (LTβ) is highly expressed in tumour cells within the bone microenvironment and this expression is associated with poor bone metastasis-free survival. LTβ promotes tumour cell colonization and outgrowth in multiple Breast Cancer Models. Mechanistically, tumour-derived LTβ activates osteoblasts through nuclear factor-κB2 signalling to secrete CCL2/5, which facilitates tumour cell adhesion to osteoblasts and accelerates osteoclastogenesis, leading to bone metastasis progression. Blocking LTβ signalling with a decoy receptor significantly suppressed bone metastasis in vivo, whereas clinical sample analysis revealed significantly higher LTβ expression in bone metastases than in primary tumours. Our findings highlight LTβ as a bone niche-induced factor that promotes tumour cell colonization and osteolytic outgrowth and underscore its potential as a therapeutic target for patients with bone metastatic disease.

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