Looking into the Crystal Ball: Uncovering Predictive Mechanical Cues for Cell Choices in Development and Disease'

我们身体的细胞和组织不断地被推拉，它们适当地感知和响应这些机械力，以维持正常的组织功能，这是至关重要的。在胚胎发生期间尤其如此，胚胎发生是从单个细胞生长和塑造整个有机体的独特复杂过程。我们开始了解一些将细胞行为与孤立细胞中的机械力联系起来的细胞机制，但我们对这一机制如何应用于我们身体的复杂组织知之甚少。弥合这一差距很重要，因为许多常见疾病，如癌症，会改变我们组织的机械性能。在这个项目中，我们将研究组织的物理环境如何有助于正常的胚胎发育。从胚胎学到的经验将被应用到癌症发展的模型中，以揭示细胞和组织在肿瘤发生过程中如何维持或失调对机械力的反应。我们将使用尖端显微镜和数学模型来揭开“现实世界”组织环境中机械调节的复杂性。一个重要的、“真实世界”的组织环境是哺乳动物的神经脊。神经脊细胞(NCC)是一种高度迁移和多潜能的细胞群，在胚胎发育中发挥着重要作用。来自NCC的一种关键细胞类型是黑素细胞，它是皮肤中产生色素的细胞，也是黑色素瘤的母细胞，黑色素瘤是一种毁灭性的皮肤癌。我们将使用胚胎黑素细胞发育的转基因荧光报告鼠模型(iDct-GFP)。通过在共聚焦成像下对组织外植体施加可重复性的力，我们将绘制在已知的力机制下小鼠黑素细胞前体组织中细胞形状的变化。我们的目的是探索拉伸组织外植体中机械力和动态细胞行为之间的关系。这项工作将在尖端的活体成像方面继续进行，以观察整个和活着的胚胎中的黑素细胞谱系，以及早期肿瘤进展的小鼠黑色素瘤模型。这项工作将受益于与世界领先的活体内专家Roberto Weigert博士(美国NCI，NIH)和享有盛誉的小鼠黑色素瘤模型权威Glenn Merlino博士(NCI，NIH，美国)的密切合作。该项目将包括对美国国立卫生研究院校园的潜在访问，以进一步发展技术/合作。这项工作有可能发现早期黑色素瘤转移风险的有意义的预测因子，这将彻底改变选择患者肿瘤进行进一步治疗的方式。该项目符合BBSRC“推进生物科学发现前沿”的任务，涉及两个优先领域：1.了解生命规则：我们的组织存在于动态的物理环境中，它们感知和响应机械力的能力对正常功能至关重要。在这个项目中，我们将确定这些物理的“生命规则”如何在复杂的组织环境中调节细胞的行为。我们的目标是揭示可以预测未来细胞行为(如增殖、世系承诺)的简单物理标记(例如细胞几何)2.变革性技术：我们将使用先进的体内/活体成像来跟踪复杂组织中的细胞行为，并将其与数学模型相结合来推断机械应力。通过将机械特性映射到细胞行为(反之亦然)，我们最终的目标是建立新的工具来预测单个细胞如何对其组织微环境做出反应

The cells and tissues of our bodies are constantly pushed and pulled and it is vital that they sense and respond to these mechanical forces appropriately to maintain normal tissue function. This is particularly true during embryogenesis - the uniquely complex process of growing and shaping a whole organism from a single cell. We are beginning to understand some of the cellular mechanisms that link cell behaviour with mechanical force in isolated cells, but we know much less about how this applies to the complex tissues of our bodies. Bridging this gap is important since many common diseases, such as cancer, alter the mechanical properties of our tissues. In this project we will study how the physical environment of a tissue contributes to normal embryo development. Lessons learned from the embryo will then be applied to models of cancer development to reveal how cell and tissue responses to mechanical force are maintained or dysregulated during oncogenesis.We will use cutting-edge microscopy and mathematical modelling to unlock the complexity of mechano-regulation in "real-world" tissue environments. One fundamentally important, "real-world" tissue environment is the mammalian neural crest. Neural Crest Cells (NCCs) are a highly migratory and multipotent population of cells that play a major role in embryonic development. A crucial cell type derived from NCCs are melanocytes, which are pigment-producing cells in skin and the parent cell of melanoma, a devastating skin cancer. We will use a transgenic, fluorescent reporter mouse model (iDct-GFP) of embryonic melanocyte development. By applying a reproducible force to tissue explants under confocal imaging, we will map cell-shape changes in the mouse melanocyte precursor tissues when under known force regimes. We aim to explore the relationship between mechanical force and dynamic cell behaviours in the stretched tissue explants. This work will be taken forward in cutting-edge intravital imaging to observe the melanocytic lineage in a whole and living embryo and in mouse melanoma models of early tumour progression. This work will benefit from strong collaborations with the world-leading intravital expert, Dr Roberto Weigert (NCI, NIH, USA) and with the prestigious mouse melanoma model authority, Dr Glenn Merlino (NCI, NIH, USA). This project will include a potential visit to the NIH campus, USA, to further develop the technology/collaborations. This work has the potential to uncover a meaningful predictor for metastatic risk in early-stage melanoma tumours, which would revolutionise the way patient tumours are selected for further therapy. The project fits the BBSRC remit of "Advancing the frontiers of bioscience discovery" by addressing two priority areas:1. Understanding the rules of life: Our tissues exist in dynamic physical environments and their ability to sense and respond to mechanical force is vital for normal function. In this project we will determine how these physical "rules of life" regulate cell behaviour in complex tissue environments. We aim to reveal simple physical markers (e.g. cell geometry) that can predict future cell behaviour (e.g. proliferation, lineage commitment)2. Transformative technologies: We will use cutting edge in vivo/intravital imaging to track cell behaviour in complex tissues and combine this with mathematical modelling to infer mechanical stress. By mapping mechanical properties onto cell behaviours (and vice versa) we ultimately aim to build new tools to predict how individual cells will respond to their tissue microenvironment