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

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.

Unique cellular protrusions mediate breast cancer cell migration by tethering to osteogenic cells

“…5a). This approach was previously utilized to screen for drugs that selectively target cancer-bone interactions 35 . Using MCF-7 cells and IIA injection, we could detect , respectively.…”

GALC Triggers Tumorigenicity of Colorectal Cancer via Senescent Fibroblasts

“…As fibroblasts are the most abundant cell type in the tumor stroma, the deregulation of secreted paracrine factors from fibroblasts has been shown to influence the growth, invasion, and metastasis of cancer cells (7). While several mechanisms have been reported for the regulation of cancers by senescent fibroblasts (8)(9)(10), it is clear that additional mechanisms also contribute to the stromal regulation of cancers, and thus, additional studies are warranted.…”

Novel and Conventional Preclinical Models to Investigate Bone Metastasis

“…Marlow and colleagues have established an in vitro dormancy model with a co-culture of breast cancer cells and bone cells, and identified factors that keep cells in proliferatory or inhibitory (dormant) states [39]. Novel models combining in vivo to in vitro approaches include a bone-in-culture model by Wang and colleagues [40] where cancer cells are inoculated to the intra-iliac artery. After tumor is established, bones are cut into small pieces and placed in 96-well plates that can then be used for example for drug screening purposes [40].…”

“…Novel models combining in vivo to in vitro approaches include a bone-in-culture model by Wang and colleagues [40] where cancer cells are inoculated to the intra-iliac artery. After tumor is established, bones are cut into small pieces and placed in 96-well plates that can then be used for example for drug screening purposes [40]. In the same paper, the authors also showed correlation of drug responses in the established in vitro model and an in vivo bone metastasis model [40].…”

“…After tumor is established, bones are cut into small pieces and placed in 96-well plates that can then be used for example for drug screening purposes [40]. In the same paper, the authors also showed correlation of drug responses in the established in vitro model and an in vivo bone metastasis model [40]. The novel use of the chorioallantoic membrane (CAM) model in the context of prostate cancer invasion and bone metastasis is also an interesting addition to the model portfolio [41].…”