淋巴毒素-β促进乳腺癌骨转移定植和骨溶解性生长

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

NATURE CELL BIOLOGY

影响因子:19.1

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

DOI: 10.1038/s41556-024-01478-9

摘要

骨转移是乳腺癌的致命后果之一。本研究利用单细胞转录组学研究骨转移定植这一转移级联反应中的速控步骤。我们发现淋巴毒素-β（LTβ）在骨微环境中的肿瘤细胞中高表达，且这种表达与骨转移无病生存期较差相关。LTβ促进肿瘤细胞在多种乳腺癌模型中的定植和生长。从机制上讲，肿瘤源性LTβ通过核因子-κB2信号激活成骨细胞，促使其分泌CCL2/5，从而促进肿瘤细胞粘附于成骨细胞并加速破骨细胞生成，推动骨转移的进展。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。我们的研究强调LTβ作为一个骨微环境诱导的因子，促进肿瘤细胞定植和骨溶解性生长，提示其作为骨转移疾病患者的潜在治疗靶点具有重要意义。

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.