Center for Cancer Biology, School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Department of Orthopedic Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Nat Cell Biol. 2024 Sep;26(9):1597-1612. doi: 10.1038/s41556-024-01478-9. Epub 2024 Aug 15.
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.
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——这是转移级联中的限速步骤。我们发现，淋巴毒素-β（LTβ）在骨微环境中的肿瘤细胞中高度表达，这种表达与骨转移无复发生存率差相关。LTβ促进多种乳腺癌模型中的肿瘤细胞定植和生长。从机制上讲，肿瘤衍生的 LTβ 通过核因子-κB2 信号激活成骨细胞分泌 CCL2/5，从而促进肿瘤细胞与成骨细胞的黏附并加速破骨细胞形成，导致骨转移进展。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 表达明显高于原发肿瘤。我们的研究结果强调 LTβ 作为一种骨龛诱导因子，促进肿瘤细胞定植和溶骨性生长，并突出其作为骨转移疾病患者治疗靶点的潜力。
