A multi-cellular 3D model of human breast tissue to replace rodent xenograft models in breast cancer research.

人类乳腺组织的多细胞 3D 模型可替代乳腺癌研究中的啮齿动物异种移植模型。

• 批准号: NC/N001583/1
• 负责人: Cathy Merry
• 金额: $ 45.45万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FN001583%2F1
• 关键词: multi; cellular; 3D; model; human

The cells that make up the tissues of your body are surrounded by a matrix of proteins and sugars. Cells interact with this matrix environment helping organs fulfil their function reacting to the elasticity and stiffness of the matrix and secreting messenger molecules into the matrix leaving specific information for other cells. This complex communication is crucial during development of an embryo driving the segmentation of the body into organs and to divide organs into functional regions. The matrix also plays an important role in disease progression where cells digest proteins or sugars within the matrix to release cryptic fragments that can instruct cells to multiply or to migrate, both features that are exaggerated in the progression to cancer. Scientists have specialised techniques that can interpret messages within cells, these are often carried out in human cells grown on plastic (2D) which would not include matrix interactions. To understand 3D matrix-driven signalling they often rely on animal-derived artificial matrices that can be hard to work with due to high variability or use animal models including the growth of human cells transplanted as a xenograft into a mouse. Although these 3D assays are an improvement from 2D culture neither fully reproduce the complex human tissue matrix. There is a need to improve the 3D growth of cells within the laboratory and reduce the need for animal models that do not represent human tissue. To this end we have developed a fully synthetic, highly reproducible gel that can be decorated with proteins and sugars to mimic the matrix of human tissues. Cancer cells, along with other cells types found in native tissues, can then be encapsulated in the gels and easily grown in the lab. The development of our bespoke human matrix will provide scientists with cheap, functional and robust test environments where cancer cell behaviour can be studied in a human body mimick. This allows researchers to test theories of how cancers develop, discover new targets for intervention and additionally will provide more realistic test environments for screening therapeutics. To test our bespoke gel environments we are using breast cancer as a model system, which can we investigated in its normal, pre-invasive and invasive cancer forms. We will characterise the differences in matrix between dense and non-dense breast tissue (normal and cancer) as evidence shows that dense breast tissue is a major risk factor for breast cancer. We will then use this information to decorate gels with specific proteins and sugars to mimic these distinct matrix environments, by encapsulating cancer cells and pre-cancerous cells in the gels (along with other cell types typical of the tissue) we hope to better understand why this is and what role is played by specific proteins and sugars in the matrix. This project brings together an interdisciplinary team of cancer biologists, materials scientists and clinicians to develop a new solution that we hope will have impact for the study multiple cancer types once proven as a robust model for breast cancer we anticipate significantly reducing the numbers of animals used in xenograft studies across the world.

组成身体组织的细胞被蛋白质和糖的基质包围。细胞与该基质环境相互作用，帮助器官履行其功能，对基质的弹性和刚度做出反应，并将允许分子分泌到矩阵中，留下其他细胞的特定信息。这种复杂的交流在开发胚胎的发展过程中至关重要，将身体分割成器官并将器官分为功能区域。该基质在疾病进展中也起着重要作用，在疾病进程中，细胞消化基质中的蛋白质或糖以释放可以指示细胞繁殖或迁移的隐性片段，这两个特征都夸大了癌症的进展。科学家具有可以解释细胞内的信息的专业技术，这些技术通常是在塑料（2D）生长的人类细胞中进行的，这不包括基质相互作用。为了了解3D基质驱动的信号传导，他们通常依赖于动物来源的人造矩阵，由于变异性高或使用动物模型，包括将人类细胞作为异种移植移植到小鼠中，因此很难使用。尽管这些3D分析是2D培养的改进，但既不完全重现复杂的人体组织基质。需要改善实验室内细胞的3D生长，并减少对不代表人体组织的动物模型的需求。为此，我们开发了一种完全合成的，高度可重复的凝胶，可以用蛋白质和糖装饰，以模仿人体组织的基质。癌细胞以及在天然组织中发现的其他细胞类型，然后可以封装在凝胶中，并在实验室中很容易生长。我们定制的人类矩阵的发展将为科学家提供廉价，功能性和健壮的测试环境，在这些环境中，可以在模仿人体中研究癌细胞行为。这使研究人员可以测试癌症如何发展的理论，发现新的干预目标，并将为筛查治疗剂提供更现实的测试环境。为了测试我们定制的凝胶环境，我们将乳腺癌用作模型系统，我们可以以正常，侵入性和侵入性癌症形式进行研究。我们将表征密集和非密集乳腺组织（正常和癌症）之间基质的差异，因为证据表明密集的乳腺组织是乳腺癌的主要危险因素。然后，我们将使用这些信息用特定的蛋白质和糖来装饰凝胶，以模仿这些不同的基质环境，通过封装凝胶中的癌细胞和前癌细胞（以及组织的其他细胞类型）中的癌细胞和前癌细胞，我们希望更好地理解为什么在矩阵中的特定蛋白质和糖会起到哪些作用，并且在矩阵中发挥了什么作用。该项目汇集了一个癌症生物学家，材料科学家和临床医生的跨学科团队，以开发一种新解决方案，我们希望该研究能够对研究产生多种癌症类型的影响，曾经证明是乳腺癌的强大模型，我们预计我们预计在全球异种移植研究中使用的动物数量会大大减少。