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，女性死于乳腺癌的人数超过了胰腺癌、食道癌和脑癌的总和。乳腺癌发生的主要驱动因素仍不清楚。年龄过后，主要的风险因素之一是乳房X光检查密度，这是乳腺癌风险的公认生物标记物。这增加了癌症风险增加的可能性，部分原因是乳腺上皮细胞机械信号转导的改变。机械信号转导是细胞生物学中一个公认的概念。细胞不仅对可溶信号做出反应，如生长因子和细胞因子，还对其微环境的机械特性做出反应。在乳腺癌中，已经证明与肿瘤相关的细胞外基质的僵硬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，与乳腺摄影密度增加相关的机械信号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。目前的动物/生物衍生水凝胶模型(例如：Matrigel/藻酸盐)的一个重要限制是它们的组成在不同批次之间差异很大，并影响培养的重复性。其次，污染物和信号的高含量掩盖了细胞分泌的蛋白质的任何变化，阻碍了蛋白质组分析。因此，就目前这些复合凝胶所能做的而言，该领域已经达到了极限。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多肽水凝胶之间的相互作用，并设计新的功能系统，使其能够在体内模拟乳腺组织的细胞结构(乳腺腺泡细胞)的发育。这些将被用来研究癌症发展的触发因素，主要集中在机械信号转导上。该项目将开发完全定义的基于多肽的水凝胶模型来模拟三维乳腺组织，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：自组装多肽水凝胶系统在体外促进正常乳腺上皮细胞黏附、生长和组装成腺泡的最佳生物力学和生化特性是什么？这种改变仅水凝胶的生物力学特性是否足以促进癌症发生？什么是癌症发展的机械信号触发因素？研究的新工程和/或物理科学内容：对于这个项目，我们将利用水凝胶和监督团队广泛的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，并将表征乳腺上皮细胞的表型。

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.