Background: Breast cancer is the leading cause of death in women under 65 in New Zealand, (NZ) causing a high burden of disease and disproportionately affecting Māori and Pasifika patients. Improving our understanding of breast cancer biology, patient treatment responses and resistance, through clinically relevant tumour models could contribute to improved patient health outcomes and open up avenues for precision medicine. Breast tumours exist as a heterogenous collection of cancerous cells and non-malignant cells, including immune cells such as tumour-associated macrophages (TAMs), collectively termed the tumour microenvironment. TAMs can polarise into a pro-inflammatory or pro-tumour state and may influence treatment responses. However, more physiologically relevant models are required to better understand their role in breast cancer.
Objectives: To optimise and validate two NZ-specific patient-derived breast cancer models; patient-derived explants (PDEs), and 3D primary tumour organoids, and evaluate their potential to explore tumour-immune interactions. PDEs are 1mm3 pieces of freshly-resected tumour tissue cultured in 3D on gelatin sponges, preserving the native tumour architecture and microenvironment. Alternatively, tumour organoids are patient-derived cancer stem cells cultured in a 3D extracellular matrix, which retain the key histological and genetic features of the donor tumour.
Results: Immunohistochemistry of PDEs has demonstrated explants remain viable for up to 10 days in culture, while maintaining receptor expression, proliferative capacity and immune cell infiltration. Tumour cell death can be induced by treatment with chemotherapy and HER2-targeted therapy, demonstrated via fluorescent TUNEL assays. Multiplex immunofluorescence staining to determine immune cell infiltrate and the effect on patient-drug responses is underway, followed by spatial transcriptomics to map cancer-immune interactions. Development of a primary murine organoid-macrophage co-culture model has demonstrated profound heterogeneity in macrophage-cancer cell interactions, with 3D microscopy suggesting macrophages provide protection from chemotherapy-induced cytotoxicity. Experiments are underway to further characterise these interactions and determine the influence of TAM polarisation states.
Discussion: These models may offer new insights into tumour heterogeneity and the pro-tumorigenic role of the breast tumour microenvironment. Extending these experiments in a complimentary human organoid-macrophage 3D model may will further uncover the influence of macrophages on patient-specific drug responses.