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

Wang, X.; Zhang, T.; Zheng, B.; Lu, Y.; Liang, Y.; Xu, G.; Zhao, L.; Tao, Y.; Song, Q.; You, H.; Hu, H.; Li, X.; Sun, K.; Li, T.; Zhang, Z.; Wang, J.; Lan, X.; Pan, D.; Fu, Y.-X.; Yue, B.; Zheng, H.

doi:10.1101/2023.08.15.553179

bioRxiv · 10.1101/2023.08.15.553179

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

Wang, X.·Zhang, T.·Zheng, B.·Lu, Y.·Liang, Y.·Xu, G.·Zhao, L.·Tao, Y.·Song, Q.·You, H.·Hu, H.·Li, X.·Sun, K.·Li, T.·Zhang, Z.·Wang, J.·Lan, X.·Pan, D.·Fu, Y.-X.·Yue, B.·Zheng, H.

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Abstract

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, LT{beta} (lymphotoxin-{beta}) 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 LT{beta} activates NF-{kappa}B2 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 LT{beta} signaling with a decoy receptor significantly suppressed bone colonization and metastatic progression, whereas clinical sample analysis revealed significantly higher LT{beta} expression in bone metastases than in primary tumors. Our findings highlight LT{beta} 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.

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Wang, X., Zhang, T., Zheng, B., Lu, Y., Liang, Y., Xu, G., Zhao, L., Tao, Y., Song, Q., You, H., Hu, H., Li, X., Sun, K., Li, T., Zhang, Z., Wang, J., Lan, X., Pan, D., Fu, Y.-X., Yue, B., Zheng, H.. 2023-08-16. Lymphotoxin-β Promotes Bone Colonization and Osteolytic Outgrowth of Indolent Bone Metastatic cells of Breast Cancer. https://doi.org/10.1101/2023.08.15.553179

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