Physical role of the nucleus in cell migration

Understanding how metastatic cancer cells move will enable the search for therapies targeting secondary tumour forming cells. Recent experiments suggest that the cell nucleus, which is disrupted and generally much softer in cancerous cells compared to healthy cells, plays an important role in cell migration. Specifically the nucleus is thought to be involved in setting or maintaining the direction of cell motion. Connections between the nucleus and the cytoskeleton (the main structural body of the cell) appear to be essential for migration in soft 3D tissue-like environments. Finally whether or not the nucleus gets stuck determines whether a cell successfully squeezes through constrictions. This project will develop theoretical models whose predictions, once tested, will determine the physical roles of the nucleus in cell migration. From a physics perspective the cell cytoskeleton can be described as a soft gel-like material that is "active" or "out of equilibrium" meaning it is consuming biochemical energy. This type of material has been successfully described by the recently developed theory of "active gels", which has already proved useful in modelling cell movement. Usually in such models the nucleus of the cell is ignored and the cell is treated as a single material, however this project specifically addresses the role of the nucleus. Understanding the mechanical roles of a passive elastic object embedded in an active fluid is a challenging problem within the emerging field of the physics of active (out of equilibrium) matter. Elucidating the physical roles of the nucleus in cell migration will make an important contribution to the grand challenge of understanding the physics of life.

The potential scale of the impact of this project is very large due to the enormity of the problem of metastatic cancer (28% of UK deaths in 2010 were caused by cancer, 90% of which due to metastasis). This project will contribute to the body of knowledge needed to guide future healthcare technologies that target migrating metastatic, secondary tumour forming cells. The main societal beneficiaries of this work will therefore be cancer patients and the NHS and the main economic beneficiaries will be the pharmaceutical and healthcare technologies industries. Should the research objectives discussed in this proposal be achieved this will inform further future research into normal and cancerous cell motility, which in turn will impact cancer medicine development. Such further research would guide the search for new targets and healthcare technologies leading to new therapies. We therefore expect that the main benefits of this work will be seen on the long term (20+ years).