The 2025 Jane Tomlinson Appeal NBCRC Pilot Grant awarded to Dr Sarah Storr - The use of advanced 3D models to understand bone colonising breast cancer
Lay summary
Background: Breast cancer is one of the most prevalent cancers globally, and when it spreads, the bone is often its first destination. Even in early stage disease, tiny clusters of cancer cells can hide in the bones,remaining dormant for years. Understanding how cancer not only spreads but also survives in the bone is critical for developing more effective treatment strategies.
Aims: This research will create models that accurately mimic the bone environment in patients, allowing scientists to study how breast cancer spreads and grows during bone metastasis. We will use powerful techniques to explore gene expression levels and metabolite changes in individual cells to discover pathways involvedin facilitating and regulating bone metastasis.
Techniques: We will use 3D printing to create bone-like structures that will be seeded with special cells to produce and mimic bone. We will then add different types of breast cancer cells, from different disease phenotypes, to see how they interact with the bone-like tissue. Using single-cell RNA sequencing and single-cell metabolomics, wewill analyse the levels of gene expression and metabolite levels inindividual cancer cells to understand what makes them able to survive and colonise bone.
Impact: This study will develop new ways to study bone metastasis in thelaboratory, allowing us to understand how breast cancer colonisesbone. By identifying important genes and metabolites involved inthe process, we will discover new ways to treat patients with bonemetastasis. The long-term aim of this research is to stop the spreadof breast cancer and improve survival of patients with secondarycancer. This research will also contribute to the development ofbetter cell culture models and help researchers work together bysharing findings, leading to faster breakthroughs in cancertreatment.
Scientific summary
Background: Breast cancer remains one of the most prevalent cancers globally, and metastasis is the leading cause of mortality in patients. Bone isthe most common site of metastasis, affecting 70% of patients, and is more frequently observed in patients with oestrogen receptor(ER) positive tumours. Research into breast cancer metastasis predominantly relies onanimal models due to the limitations of existing in vitro models in replicating the intricate 3D bone micro environment. In vivo models provide important information on the process of metastasis, although limitations include the lack of spontaneous bone metastasis of primary mammary tumours, no syngeneic models ofER+ disease, and a focus on ER- breast cancer in immunodeficient models.
Aims: This study will develop state-of-the-art 3D-printed in vitro models of breast cancer bone colonisation that accurately mimic human bone physiology. We will leverage single-cell RNA-seq and metabolomics to uncover transcriptomic and metabolomic signatures associated with bone colonisation.
Techniques and Methodology: Trabecular bone-like scaffolds will be fabricated using multiphoton polymerisation 3D bioprinting, with human mesenchymal stromal cells induced into osteogenic differentiation. These scaffolds will support co-culture systems involving ER- (MDA-MB-231) and ER+ (MCF-7 and T47D) breast cancer cell lines. Single-cellRNA-seq and metabolomics will identify changes that occur during the bone colonisation process.
Impact on breast cancer research: This research will establish a more physiologically relevant 3D platform, providing insights into the molecular mechanisms underlying breast cancer colonisation of bone. By identifyingcritical transcriptomic and metabolic pathways, the study has the potential to uncover novel therapeutic targets, ultimately advancing treatment strategies and improving outcomes for breastcancer patients with bone metastases.