Title | Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Zheng, H, Bae, Y, Kasimir-Bauer, S, Tang, R, Chen, J, Ren, G, Yuan, M, Esposito, M, Li, W, Wei, Y, Shen, M, Zhang, L, Tupitsyn, N, Pantel, K, King, C, Sun, J, Moriguchi, J, Jun, HToni, Coxon, A, Lee, B, Kang, Y |
Journal | Cancer Cell |
Volume | 32 |
Issue | 6 |
Pagination | 731-747.e6 |
Date Published | 2017 Dec 11 |
ISSN | 1878-3686 |
Keywords | Animals, Antibodies, Monoclonal, Antineoplastic Agents, Bone Neoplasms, Humans, Jagged-1 Protein, Mice, Mice, Transgenic, Osteoblasts, Xenograft Model Antitumor Assays |
Abstract | <p>Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.</p> |
DOI | 10.1016/j.ccell.2017.11.002 |
Alternate Journal | Cancer Cell |
PubMed ID | 29232552 |
PubMed Central ID | PMC5729937 |
Grant List | R01 CA212410 / CA / NCI NIH HHS / United States T32 GM007388 / GM / NIGMS NIH HHS / United States |