Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies

Hai Wang, Lin Tian, Amit Goldstein, Jun Liu, Hin-Ching Lo, Kuanwei Sheng, Thomas Welte, Stephen T.C. Wong, Zbigniew Gugala, Fabio Stossi, Chenghang Zong, Zonghai Li, Michael A. Mancini and Xiang H.-F. Zhang ()
Additional contact information
Hai Wang: Lester and Sue Smith Breast Center, Baylor College of Medicine
Lin Tian: Lester and Sue Smith Breast Center, Baylor College of Medicine
Amit Goldstein: Lester and Sue Smith Breast Center, Baylor College of Medicine
Jun Liu: Lester and Sue Smith Breast Center, Baylor College of Medicine
Hin-Ching Lo: Lester and Sue Smith Breast Center, Baylor College of Medicine
Kuanwei Sheng: Department of Molecular and Human Genetics
Thomas Welte: Lester and Sue Smith Breast Center, Baylor College of Medicine
Stephen T.C. Wong: Houston Methodist Research Institute, Weill Cornell Medical College
Zbigniew Gugala: University of Texas Medical Branch
Fabio Stossi: Dan L. Duncan Cancer Center, Baylor College of Medicine
Chenghang Zong: Dan L. Duncan Cancer Center, Baylor College of Medicine
Zonghai Li: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Michael A. Mancini: Dan L. Duncan Cancer Center, Baylor College of Medicine
Xiang H.-F. Zhang: Lester and Sue Smith Breast Center, Baylor College of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract The majority of breast cancer models for drug discovery are based on orthotopic or subcutaneous tumours. Therapeutic responses of metastases, especially microscopic metastases, are likely to differ from these tumours due to distinct cancer-microenvironment crosstalk in distant organs. Here, to recapitulate such differences, we established an ex vivo bone metastasis model, termed bone-in-culture array or BICA, by fragmenting mouse bones preloaded with breast cancer cells via intra-iliac artery injection. Cancer cells in BICA maintain features of in vivo bone micrometastases regarding the microenvironmental niche, gene expression profile, metastatic growth kinetics and therapeutic responses. Through a proof-of-principle drug screening using BICA, we found that danusertib, an inhibitor of the Aurora kinase family, preferentially inhibits bone micrometastases. In contrast, certain histone methyltransferase inhibitors stimulate metastatic outgrowth of indolent cancer cells, specifically in the bone. Thus, BICA can be used to investigate mechanisms involved in bone colonization and to rapidly test drug efficacies on bone micrometastases.

Date: 2017
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DOI: 10.1038/ncomms15045

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