Engineering the bone marrow niche to control stem cell regulation, metastatic evolution and cancer dormancy

改造骨髓生态位来控制干细胞调节、转移进化和癌症休眠

• 批准号: EP/X036049/1
• 负责人: Matthew Dalby
• 金额: $ 782.98万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX036049%2F1
• 关键词: Engineering; bone; marrow; niche; control

The bone marrow is a site of health and disease. In health, it produces all of the blood cells that we rely on to carry oxygen and protect us from infection. However, the stem cells that produce the blood and that reside in the marrow, the haematopoietic stem cells (HSCs), age and can tip over into disease states, such as developing leukaemia. Factors such as smoking and treatment of cancers elsewhere in the body (toxic effects of chemotherapy/radiotherapy) can accelerate ageing, and therefore, drive the transition to disease. Further, it forms a home to other cancer cells, that leave their original tumour and move, or metastasise, to the bone marrow. Once in the marrow, they can become dormant, hiding from chemotherapies and activating sometime later to form devastating bone cancers. The cues that wake cancer cells from dormancy are largely unknown.If models of the bone marrow that contain human cells and that can mimic key facets of the niche in the lab, such as blood regeneration, cancer evolution and dormancy, can be developed it would be a big help in the search for better cancer therapies. We are developing the materials and technologies required to meet this challenge. In this programme of research, we will tackle three biomedical challenges:1) HSC regeneration. Bone marrow transplantation (more correctly HSC transplantation) is a one-donor, one-recipient therapy that can be curative for blood diseases such as leukaemia. It is limited as HSCs cannot be looked after well out of the body. Approaches to properly look after these precious cells in the lab could allow this key therapy to become a one-donor, multiple recipient treatment. Further, the ability to look after the cells in the lab would open up the potential for genetically modifying the cells to allow us to cure the cells and put them back into the patient, losing the need for patient immunosuppression.2) Cancer evolution. As we get older, our cells collect mutations in their DNA and these mutations can be drivers of cancer. Lifestyle choices such as smoking, and side effects of treatments of other diseases can also add mutations to the cells. As blood cancers develop, the bone marrow changes its architecture to protect these diseased HSCs. Our 3D environments will allow us to better understand this marrow remodelling process and how drugs can target cancers in this more protective environment. The models will also allow us to study the potential toxicity of gene-edited HSCs to make sure they don't produce unwanted side effects or are not cancerous in themselves.3) Dormancy. What triggers dormancy and activation from dormancy are poorly understood. By placing our 3D environments in a miniaturised format where we can connect other models that include infection and immune response, we can start to understand the factors involved in the activation of cancer cells from dormancy.Our vision is driven by materials and engineering, as the bone marrow niche is rich in structural and signalling biological materials (proteins). Therefore, we will establish three engineering challenges:(1) Cells can be controlled by the stiffness and viscous nature of materials (viscoelasticity). We will therefore develop synthetic-biological hybrid materials that can be manufactured to have reproducible physical properties and that have biological functionality. (2) We will develop these materials to interact with growth factors and bioactive metabolites, both of which are powerful controllers of cell behaviours. These materials will be used to assemble the HSC microenvironments in lab-on-chip (miniaturised) format to allow high-content drug and toxicity screening. (3) We will develop real-time systems to detect changes in cell behaviour, such as the transition from health to cancer using Raman and Brillouin microscopies.The use of animals in research provides poor predictivity. We will offer better than animal model alternatives.

骨髓是健康和疾病的部位。在健康方面，它会产生我们依靠的所有血细胞来携带氧气并保护我们免受感染的影响。然而，产生血液并驻留在骨髓中的干细胞，造血干细胞（HSC），年龄，可以倾斜到疾病状态，例如发展性白血病。诸如吸烟和治疗体内其他地方的癌症（化学疗法/放射疗法的毒性作用）等因素可以加速衰老，因此可以推动过渡到疾病的过渡。此外，它形成了其他癌细胞的家园，它们会使其原始的肿瘤并移动或转移到骨髓。进入骨髓后，它们可能会休眠，躲藏在化学疗法中并在某个时候激活以形成毁灭性的骨癌。如果含有人体细胞的骨髓模型并可以模仿实验室中利基市场的关键方面，例如血液再生，癌症的进化和休眠，则可以开发出含有人体细胞的骨髓模型。我们正在开发应对这一挑战所需的材料和技术。在这个研究计划中，我们将解决三个生物医学挑战：1）HSC再生。骨髓移植（更正确的是HSC移植）是一种单位，一种院疗法，可以治愈白血病等血液疾病。它受到限制，因为HSC不能像从体内那样照顾。适当照顾实验室中这些贵重细胞的方法可以使这种关键的疗法成为一种单位，多个受体治疗。此外，照顾实验室中细胞的能力将打开基因修饰细胞以使我们能够治愈细胞并将其放回患者的潜力，从而失去了对患者免疫抑制的需求。2）癌症的演变。随着年龄的增长，我们的细胞在其DNA中收集突变，这些突变可能是癌症的驱动因素。诸如吸烟和其他疾病治疗的副作用之类的生活方式选择也会为细胞增加突变。随着血液癌的发展，骨髓会改变其建筑以保护这些患病的HSC。我们的3D环境将使我们能够更好地理解这种骨髓的重塑过程，以及在这种更具保护性环境中的药物如何靶向癌症。这些模型还将使我们能够研究基因编辑的HSC的潜在毒性，以确保它们不会产生不必要的副作用或本身不会癌。3）休眠。触发休眠和休眠激活的原因知之甚少。通过将3D环境放置在微型化的格式中，我们可以连接其他模型（包括感染和免疫反应），我们可以开始了解癌细胞因休眠而激活癌细胞的因素。您的视觉是由材料和工程驱动的，因为骨髓壁niche富含结构和信号生物学材料（蛋白质）。因此，我们将建立三个工程挑战：（1）细胞可以通过材料的刚度和粘性（粘弹性）来控制。因此，我们将开发合成生物杂种材料，可以制造具有可重现的物理特性并具有生物学功能。 （2）我们将开发这些材料以与生长因子和生物活性代谢产物相互作用，这两者都是细胞行为的强大控制器。这些材料将用于以实验室片（小型化）格式组装HSC微环境，以允许高内含药物和毒性筛选。 （3）我们将开发实时系统来检测细胞行为的变化，例如使用拉曼和布里鲁因显微镜从健康到癌症的过渡。我们将提供比动物模型替代品更好的。