清华大学郑撼球等研究人员合作发现，淋巴毒素-β促进乳腺癌骨转移的定植和溶骨性生长。该研究于2024年8月15日在线发表于国际一流学术期刊《自然—细胞生物学》。

研究人员表示，骨转移是乳腺癌的致命后果。

研究人员通过单细胞转录组学研究了骨转移定植这一转移级联反应中的限速步骤的分子机制。

研究人员发现淋巴毒素-β（LTβ）在骨微环境中的肿瘤细胞中高度表达，并且这种表达与较差的骨转移无病生存率相关。LTβ在多种乳腺癌模型中促进了肿瘤细胞的定植和生长。

在机制上，肿瘤来源的LTβ通过核因子-κB2信号通路激活成骨细胞，诱导其分泌CCL2/5，这些化学因子促进肿瘤细胞与成骨细胞的粘附并加速破骨细胞生成，从而推动骨转移的进展。

使用诱饵受体阻断LTβ信号显著抑制了体内的骨转移，而临床样本分析显示，骨转移中的LTβ表达显著高于原发肿瘤。

这些研究结果表明，LTβ作为一种骨微环境诱导因子，促进了肿瘤细胞的定植和溶骨性生长，强调了其作为骨转移疾病患者潜在治疗靶点的可能性。

附：英文原文

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

Author: Wang, Xuxiang, Zhang, Tengjiang, Zheng, Bingxin, Lu, Youxue, Liang, Yong, Xu, Guoyuan, Zhao, Luyang, Tao, Yuwei, Song, Qianhui, You, Huiwen, Hu, Haitian, Li, Xuan, Sun, Keyong, Li, Tianqi, Zhang, Zian, Wang, Jianbin, Lan, Xun, Pan, Deng, Fu, Yang-Xin, Yue, Bin, Zheng, Hanqiu

Issue&Volume: 2024-08-15

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.

DOI: 10.1038/s41556-024-01478-9

Source: https://www.nature.com/articles/s41556-024-01478-9