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

乳腺癌仍然是英国第二大癌症死亡原因，其死亡人数超过胰腺癌，食道癌和脑癌的总和。乳腺癌发生的主要驱动因素尚不清楚。年龄之后，主要的风险因素之一是乳房X线摄影密度，这是乳腺癌风险的既定生物标志物。这就提出了一种可能性，即癌症风险的增加部分是由于乳腺上皮细胞中机械信号的改变。细胞不仅响应于可溶性信号，如生长因子和细胞因子，而且还响应于其微环境的机械特性。在乳腺癌中，已经表明与肿瘤相关的细胞外基质的刚度增加驱动癌细胞行为的变化，刺激更具侵袭性的表型。我们假设与乳腺X线摄影密度增加相关的机械信号传导的变化也可能促进正常乳腺上皮细胞行为的变化，促进致癌表型和突变的获得。当前动物/生物衍生的水凝胶模型（例如：基质胶/藻酸盐）的显著限制是它们的组成在批次之间显著变化并且影响培养物的再现性。其次，高含量的污染物和信号掩盖了细胞分泌的蛋白质的任何变化，从而阻止了蛋白质组学分析。因此，该领域已经达到了极限，可以做什么与这些目前的复合凝胶。因此，有必要开发新的完全定义的合成水凝胶模型。该项目将专注于了解乳腺上皮细胞和自组装肽水凝胶之间的相互作用，并设计新的功能系统，以允许开发模拟体内乳腺组织的细胞结构（乳腺腺泡）。这些将用于研究癌症发展的触发因素，主要关注机械信号传导。该项目将开发完全定义的基于肽的水凝胶模型来模拟3D乳腺组织，以了解与乳腺癌风险增加相关的变化。该项目试图解决的研究问题：自组装肽水凝胶系统的最佳生物力学和生物化学特性是什么，以促进正常乳腺上皮细胞在体外粘附，生长和组装成腺泡？单独改变水凝胶的生物力学性质是否足以促进癌症的发生？癌症发展的机械信号触发因素是什么？研究的新工程和/或物理科学内容：对于该项目，我们将利用水凝胶结合监督团队的广泛跨学科专业知识来设计乳腺癌启动的新模型。将使用不同硬度的水凝胶，并表征乳腺上皮细胞表型。

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.