Development of a novel "all-human" animal model to study breast cancer metastasis to bone - comparison of transcriptional signatures from ex vivo cultured primary tumor cells and in vivo metastatic populations.

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Currently, treatment options of breast cancer-related metastatic bone disease are usually restricted to palliative therapeutic modalities. Hence, there is a great need to understand the mechanisms of metastatic bone disease at a molecular level. But the currently used in vitro or in vivo models fail to represent the complex composition of the human bone matrix. In order to provide a more appropriate human-specific bone microenvironment, the so-called bone chip model, has been introduced, which relies on the subcutaneous implantation of human bone fragments into severe combined immunodeficient mice. However, this model has major limitations: The bone chip gets poorly vascularized and hence the dead bone does not reflect the real clinical situation. It is very difficult to control size and shape of the bone chip which makes it difficult to establish a reproducible model. The use of tissue engineered constructs could be a highly attractive alternative, since it allows higher reproducibility and control of shape, size and porosity. In the projected study we propose to delineate the comparative transcriptome and methylation profiling of breast cancer cells in models based on 2D & 3D cultures and xenograft tumors in immunocompromised mice. Further, in an in vivo model we propose a novel human tissue engineered bone construct to investigate osteotropism from both sides of the tumor-bone interface in addition to the comparative transcriptome and methylation profiling. This model may recapitulate the metastatic sequence occurring in patients much better than the bone chip model. In addition, we are identifying components within bone stroma essential for metastasis, and osteotropism genes expressed by bone in response to the presence of breast cancer. The proposed research will seek to address important questions in relation to the efficacy of common cancer animal models in the pre-clinical evaluation of human biomarkers and therapeutics.