Nanotopographical effects on transcriptional regulation and nuclear morphology to inform strategies against cancer

The Cancer Research Centre of Excellence (CRCE) is a strategic partnership between Imperial College London and The Institute of Cancer Research, London to drive forward advances in the detection, prevention, diagnosis and treatment of cancer.

As part of this initiative our PhD programme aims to provide training for the next generation of multidisciplinary scientists. A cross-institutional PhD project (summary below) is available for commencement in October 2018 jointly supervised by Imperial and ICR supervisors Prof Molly Stevens and Dr Chris Bakal.

To apply for this PhD you should be a graduate or final year undergraduate and hold or expect to gain a first or upper second class honours degree or equivalent, or a Masters degree, in a relevant subject. The successful candidate will undertake a four-year research training programme under the guidance of Prof Molly Stevens and Dr Chris Bakal, starting in October 2018. The student will receive an annual stipend, currently £21,000 per annum, and project costs are paid for the four-year duration. The funding covers course fees at the Home/EU rates (funding for overseas fees is not provided). 

Only recently have cellular-scale 3D structures been available for high resolution analyses of cell behaviour, particularly in regard to nuclear morphology. Prof Molly Stevens’ programme has expertise in nanotechnological innovations and their exploitation in the life sciences. Within this ICR CRCE Studentship intense research efforts will be used to characterise the effects of nano-scale structures on cell and nuclear architecture and gene expression and nanotopographical interactions at the cell-material interface.

The impact of a better understanding and control of transcription factor regulator using nanostructures and biophysical forces is enormous. Such an approach will require a deep understanding of how nano-biophysical forces affect transcriptional regulators. Only recently have we been able to perform highly informative cell population-wide studies on transcription factors that respond to cell shape perturbations. For example, YAP (Yes-associated protein), is a mechanosensitive transcriptional coactivator that drives mammalian cell growth, proliferation, differentiation and tumorigenesis. Mechanical forces from the extracellular matrix induce YAP translocation to the nucleus where it modulates gene expression, but the sensitivity of YAP to changes in cell shape makes elucidating its regulatory pathways challenging. Recently, Bakal reported an innovative multiparametric analytical approach to deconvolve these pathways, published in Cell Systems in 2017, using image-based analysis and multivariate regression that exploits the naturally occurring variability present in wild-type cells. This work showed that β-PIX and PAK2 drive YAP activation during cell spreading on 2D substrates. However, it is not known how changes in nuclear morphology impact the translocation dynamics of YAP and other mechanically-sensitive transcription factors. Stable nanostructures will allow us to reproducibly modulate nuclear morphology on an unprecedented scale. Nanopatterned surfaces engineered by the Stevens labs will be applied to cell populations to control transcriptional programs, for example to direct or inhibit stem cell differentiation, or even to integrate engineered cells into biomedical devices, which would have enormous potential beneficial impact for patients.

Within this ICR-CRCE PhD studentship we will explore a unique multidisciplinary approach to studying transcriptional regulation and nuclear morphology using powerful statistical imaging models, innovative 3D nanostructures and high resolution imaging. The student will have access to the most cutting-edge nano-fabrication equipment at Imperial, as well as a well-established framework and validated reagents for investigating the relevant signalling pathways at the ICR.

To apply for this PhD you should be a graduate or final year undergraduate and hold or expect to gain a first or upper second class honours degree or equivalent, or a Masters degree, in a relevant subject.

For further details, please visit the CRCE website, The Stevens Group and email Professor Molly Stevens.

Application are accepted all year round.