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Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies
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Journal Article
Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies
2017
Overview
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.
The bone microenvironment may alter therapeutic responses of disseminated breast cancer cells. Here the authors establish an
ex vivo
bone metastasis model, termed BICA, to delineate the effects of bone microenvironment and to rapidly discover anti-metastasis drugs.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/19
/ 14/63
/ 38/91
/ 59/5
/ Animals
/ Antineoplastic Agents - pharmacology
/ Aurora Kinases - antagonists & inhibitors
/ Benzamides - adverse effects
/ Bone and Bones - drug effects
/ Bone Neoplasms - drug therapy
/ Bones
/ Female
/ High-Throughput Screening Assays
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mammary Neoplasms, Experimental - drug therapy
/ Mammary Neoplasms, Experimental - enzymology
/ Mammary Neoplasms, Experimental - genetics
/ Mammary Neoplasms, Experimental - pathology
/ Medicine
/ Mice
/ Protein Kinase Inhibitors - pharmacology
/ Science
/ Tumors
