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

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