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Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies
Hai Wang1,2,3,4, Lin Tian1,2,3,5, Amit Goldstein1,2,3
1Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
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.
Insights
A novel bone metastasis model (BICA) accurately mimics in vivo conditions. This model identified danusertib as a promising inhibitor for bone micrometastases, while other drugs stimulated outgrowth.
Area of Science:
- Oncology
- Cancer Metastasis Research
- Drug Discovery Models
Background:
- Current breast cancer drug discovery models (orthotopic, subcutaneous) do not fully represent metastatic disease.
- Therapeutic responses in metastases may differ from primary tumors due to unique microenvironment interactions in distant organs.
- Microscopic metastases, particularly in bone, require specialized models to study their distinct biology and drug responses.
Purpose of the Study:
- To establish and validate an ex vivo bone metastasis model (bone-in-culture array, BICA) that recapitulates in vivo bone micrometastases.
- To investigate the unique cancer-microenvironment crosstalk within bone micrometastases.
- To screen potential drug candidates for efficacy against bone-specific breast cancer metastases.
Main Methods:
- Established the bone-in-culture array (BICA) model by fragmenting mouse bones preloaded with breast cancer cells via intra-iliac artery injection.
- Characterized BICA for maintenance of in vivo micrometastasis features: microenvironmental niche, gene expression, growth kinetics, and therapeutic responses.
- Performed proof-of-principle drug screening using the BICA model.
Main Results:
- The BICA model successfully maintained key features of in vivo bone micrometastases.
- Danusertib, an Aurora kinase inhibitor, preferentially inhibited bone micrometastases in the BICA model.
- Certain histone methyltransferase inhibitors were found to stimulate the outgrowth of indolent cancer cells specifically within the bone microenvironment.
Conclusions:
- The bone-in-culture array (BICA) is a valuable ex vivo model for studying bone metastasis.
- BICA can be utilized to investigate the mechanisms underlying cancer cell colonization and growth in bone.
- This model enables rapid and accurate testing of drug efficacy against bone micrometastases, revealing differential drug responses.
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