Developing new 3D-hydrogel models of the human mammary gland to investigate breast cancer initiation

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Breast cancer remains the second highest cause of cancer deaths in the UK, with it killing more women than pancreatic, oesophageal and brain cancer combined. The main drivers for breast cancer occurrence remain unclear. After age, one of the major risk factors is mammography density, which is an established biomarker of breast cancer risk. This has raised the possibility that increased cancer risk is in part due to altered mechano-signalling in mammary epithelial cells.Mechano-signalling is a well-established concept in cell biology. Cells not only respond to soluble signals, such as growth factors and cytokines, but also to the mechanical properties of their microenvironment. In breast cancer it has been shown that the increased stiffness of the extracellular matrix associated with a tumour drives changes in cancer cell behaviour, stimulating a more invasive phenotype. We hypothesise that changes in mechano-signalling associated with increased mammography density may also promote changes in normal mammary epithelial cells behaviour, promoting the oncogenic phenotype and acquisition of mutations. A significant limitation of current animal/bio derived hydrogel models (e.g: matrigel/alginate) is their composition which varies significantly between batches and affects the reproducibility of cultures. Secondly, the high content of contaminant and signals masks any changes in the proteins secreted by the cells preventing proteomic analysis. Thus, the field has reached the limit in terms of what can be done with these current composite gels. There is therefore a need to develop novel fully defined synthetic hydrogel models.The project will focus on understanding the interaction between mammary epithelial cells and self-assembling peptide hydrogel and design novel functional system that will allow the development of cellular structures (breast acini) mimicking in vivo breast tissue. These will be used to investigate the triggers for cancer development mainly focusing on mechano-signalling. This project will develop fully defined peptide-based hydrogel models to mimic 3D-breast tissue in order to understand the changes associated with increased breast cancer risk.Research questions the project is trying to address:What are the optimal biomechanical and biochemical properties of the self-assembling peptide hydrogel system to promote the adhesion, growth and assembly of normal mammary epithelial cells into acini in vitro?Is the alteration the biomechanical properties of the hydrogel alone adequate to promote initiation of cancer development? What are the mechano-signalling triggers for cancer development? Novel engineering and/or physical sciences content of the research: For this project, we will exploit hydrogels combined with the broad interdisciplinary expertise of the supervisory team to design novel models of breast cancer initiation. Hydrogel of varied stiffness will be used and the mammary epithelial cells phenotype will be characterized.