骨转移是乳腺癌的致命后果。在这里，我们使用单细胞转录组学来研究骨转移定植的分子机制——转移级联中的限速步骤。我们发现淋巴毒素-β (LTβ) 在骨微环境内的肿瘤细胞中高表达，这种表达与较差的无骨转移生存率相关。 LTβ 在多种乳腺癌模型中促进肿瘤细胞定植和生长。从机制上讲，肿瘤源性LTβ通过核因子-κB2信号传导激活成骨细胞，分泌CCL2/5，促进肿瘤细胞与成骨细胞粘附，加速破骨细胞生成，导致骨转移进展。用诱饵受体阻断 LTβ 信号传导可显着抑制体内骨转移，而临床样本分析显示骨转移中的 LTβ 表达显着高于原发肿瘤。我们的研究结果强调 LTβ 作为一种骨生态位诱导因子，可促进肿瘤细胞定植和溶骨生长，并强调其作为骨转移性疾病患者治疗靶点的潜力。© 2024。作者，获得 Springer Nature Limited 独家许可。

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.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.