Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

Hanqiu Zheng, Yangjin Bae, Sabine Kasimir-Bauer, Rebecca Tang, Jin Chen, Guangwen Ren, Min Yuan, Mark Esposito, Wenyang Li, Yong Wei, Minhong Shen, Lanjing Zhang, Nikolai Tupitsyn, Klaus Pantel, Chadwick King, Jan Sun, Jodi Moriguchi, Helen Toni Jun, Angela Coxon, Brendan LeeYibin Kang

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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. Zheng et al. develop 15D11, a fully human monoclonal antibody to Jagged1, which inhibits Jagged1 on breast cancer cells as well as blocking metastasis-promoting effects of osteoblast-derived Jagged1 induced by chemotherapy. 15D11 reduces bone metastasis and sensitizes metastases to chemotherapy in mouse models of breast cancer.

Original languageEnglish (US)
Pages (from-to)731-747.e6
JournalCancer Cell
Volume32
Issue number6
DOIs
StatePublished - Dec 11 2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Keywords

  • Jagged1
  • bone metastasis
  • breast cancer
  • chemoresistance
  • neutralizing antibody
  • osteoblastic niche
  • osteoblasts

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    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, H. T., Coxon, A., ... Kang, Y. (2017). Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy. Cancer Cell, 32(6), 731-747.e6. https://doi.org/10.1016/j.ccell.2017.11.002