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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.
Highlights
The majority of breast cancer models for drug discovery are based on orthotopic or subcutaneous tumours
Bone-in-culture array (BICA) is based on a technique that we have previously established, namely intrailiac artery (IIA) injection[13], which selectively delivers cancer cells into the hindlimbs of mice through arterial circulation
In the following paragraphs of this section, we describe several experiments performed to compare BICA with in vivo bone lesions (IVBL) introduced by IIA injection
Summary
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 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. We have recently provided evidence supporting a preosteolytic phase of bone colonization before the vicious cycle[13] In this phase, breast cancer cells, especially the luminal subtype, tightly interact with cells in the osteoblast lineage, or osteogenic cells. Osteoclasts, on the other hand, do not appear to be involved until the transition from ‘osteogenic’ lesions to ‘osteolytic’ lesions Consistent with this finding, cancer cells injected through the iliac artery soon became tightly embedded in bone tissues and could only be dissociated with protease digestion, even after bone fragmentation[14]. It represents a preclinical platform that may fill the gap between in vitro and in vivo models, and accelerate mechanistic and pharmacological studies of bone metastasis
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