Engineering a humanized bone organ model in mice to study bone metastases

Developers

Laure C. Martine, Boris M. Holzapfel, Anna v. Taubenberger, Dietmar W. Hutmacher et al.

Description of the technology

Current in vivo models for investigating human primary bone tumors and cancer metastasis to the bone rely on the injection of human cancer cells into the mouse skeleton. This approach does not mimic species-specific mechanisms occurring in human diseases and may preclude successful clinical translation.

This technology developed a protocol to engineer humanized bone within immunodeficient hosts, which can be adapted to study the interactions between human cancer cells and a humanized bone microenvironment in vivo. A researcher trained in the principles of tissue engineering will be able to execute the protocol and yield study results within 4–6 months.

Additive biomanufactured scaffolds seeded and cultured with human bone-forming cells (primary human osteoblastic cells) are implanted ectopically (subcutaneous implantation) in combination with osteogenic factors into mice to generate a physiological bone 'organ', which is partially humanized. The model comprises human bone cells and secreted extracellular matrix; however, other components of the engineered tissue, such as the vasculature, are of murine origin. The model can be further humanized through the engraftment of human hematopoietic stem cells (HSCs) that can lead to human hematopoiesis within the murine host. The humanized organ bone model has been well characterized and validated and allows dissection of some of the mechanisms of the bone metastatic processes in prostate and breast cancer.

Practical application

The most obvious application of this technology is to exploit the humanized bone environment as a preclinical in vivo model to research species-specific mechanisms in bone cancer metastases.

Besides establishing a model for fundamental cancer biology research, the objective of this protocol is to use the human tissue-engineered bone construct as a drug-testing platform to investigate specific therapies that cannot be trialed in normal rodent models because of species-related incompatibilities, e.g., in receptor-ligand interactions. The ability to use patient-derived cells may also allow application of the human tissue-engineered bone model as a patient-specific platform for investigating drug responses and interactions of osteogenic, hematopoietic and tumor cells obtained from a single donor.

Laboratories

• Queensland University of Technology (QUT), Brisbane, Queensland (Australia)
• Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg (Germany)
• George W Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta (USA)
• Institute for Advanced Study, Technical University Munich, Garching (Germany)

Links

Publications

• Martine, L.M. et al. «Engineering a humanized bone organ model in mice to study bone metastases." 12 Nature Protocols (2017): 639–663.
• Quent, v. M.C. et al. «Differential osteogenicity of multiple donor-derived human mesenchymal stem cells and osteoblasts in monolayer, scaffold-based 3D culture and in vivo." 61 Biomed. Tech. (2016): 253–266.
• Thibaudeau, L. et al. «New mechanistic insights of integrin β1 in breast cancer bone colonization." 6 Oncotarget (2015): 332–344.