Lymphotoxin-β Promotes Bone Colonization and Osteolytic Outgrowth of Indolent Bone Metastatic cells of Breast Cancer

SUMMARY Bone metastatic relapse is a lethal consequence of breast cancer, occurring years after initial diagnosis. By analyzing single-cell transcriptomes of bone-seeding tumor cells and in vivo barcoded cDNA library screening, LTβ (lymphotoxin-β) is identified as a key factor highly expressed in early-stage bone metastatic cells, associated with poor bone metastasis-free survival, and capable of promoting dormancy reactivation in multiple breast cancer models. Mechanistically, tumor-derived LTβ activates NF-κB2 signaling in osteoblasts to express CCL2/5, facilitating tumor cell seeding and accelerating osteoclastogenesis. Both processes contribute to the reactivation of dormancy and metastatic outgrowth. Blocking LTβ signaling with a decoy receptor significantly suppressed bone colonization and metastatic progression, whereas clinical sample analysis revealed significantly higher LTβ expression in bone metastases than in primary tumors. Our findings highlight LTβ as a bone niche-induced factor that promotes tumor cell seeding and dormancy reactivation, underscoring its potential as a therapeutic target for preventing bone metastatic relapse in patients with breast cancer.