淋巴毒素-β促进乳腺癌骨转移和骨化生长
Lymphotoxin-β promotes breast cancer bone metastasis colonization and osteolytic outgrowth
影响因子:19.10000
分区:生物学1区 Top / 细胞生物学1区
发表日期:2024 Sep
作者:
Xuxiang Wang, Tengjiang Zhang, Bingxin Zheng, Youxue Lu, Yong Liang, Guoyuan Xu, Luyang Zhao, Yuwei Tao, Qianhui Song, Huiwen You, Haitian Hu, Xuan Li, Keyong Sun, Tianqi Li, Zian Zhang, Jianbin Wang, Xun Lan, Deng Pan, Yang-Xin Fu, Bin Yue, Hanqiu Zheng
摘要
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研究了骨转移定殖的分子机制 - 转移性级联反应的速率限制步骤。我们确定淋巴毒素-β（LTβ）在骨微环境内的肿瘤细胞中高度表达，并且该表达与不良的无骨转移生存有关。 LTβ促进多种乳腺癌模型中的肿瘤细胞定植和产物。从机械上讲，肿瘤来源的LTβ通过核因子-κB2信号传导激活成骨细胞，从而分泌CCL2/5，这促进了肿瘤细胞粘附到成骨细胞的粘附并加速骨质质外生，从而导致骨转移。用诱饵受体阻断LTβ信号传导在体内显着抑制了骨转移，而临床样品分析显示，骨转移中的LTβ表达明显高于原发性肿瘤。我们的发现重点介绍了LTβ是骨构诱导的因子，可促进肿瘤细胞定植和骨化溶质产物，并强调其作为骨转移性疾病患者的治疗靶标的潜力。
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.