Pancreatic cancer is a very devastating disease with a very low survival rate due to the uncontrolled metastatic spread. The first step in metastasis is local invasion followed by intravasation into the blood stream. A prerequisite for these early steps is that pancreatic cancer cells gain the ability to migrate. This is driven by changes in the regulation of the actin cytoskeleton, which provides the force for cell migration. Surprisingly little is known about the molecular details of how the regulation of the actin cytoskeleton is changed to allow pancreatic cancer cells to become motile and no drugs targeting the metastatic spread of pancreatic cancer cells are available. To better understand the function of individual regulators of the actin cytoskeleton in this process high resolution live imaging of cellular protrusions during migration and invasion is necessary. The high volume of data (“big data”) from this high content imaging requires a detailed automated analysis of a plethora of parameters to transform the data into “deep data”. In this proposed project you will primarily focus on using MATLAB to develop an image analysis pipeline for high content big data analysis of pancreatic cancer cell migration and invasion. As this is a multidisciplinary project, you will be also trained in molecular biology and tissue culture techniques to use advanced microscopy to acquire the imaging data in collaboration with other members of the team. This will also allow you to better understand the entire imaging pipeline. We have been studying a regulator of the actin cytoskeleton, Lamellipodin, for several years and recently found that Lamellipodin is required for breast cancer invasion and metastasis. Thus the imaging pipeline you are developing will initially be used to uncover the function of Lamellipodin in pancreatic cancer cell migration and invasion.
You will be joining a friendly team and will be mostly based at in the Randall Centre in the modern New Hunts House at the Guy’s Campus. The basic science aspects of the project will be supervised by Dr Matthias Krause (Randall Centre) (https://www.krauselab.org). You will have regular, weekly 1:1 meeting with your supervisor, regular lab meetings, journal clubs and research seminars. The translational aspects of the project including the expertise in pancreatic cancer will be provided by Dr Debashis Sarker who can also offer the student the possibility of attending pancreatic cancer clinics to gain an insight into the challenges faced in treating pancreatic cancer patients. The student will be part of a wider pancreatic programme which runs its own symposium once a year. In addition, you will be part of the BRC PhD program and have access to the Randall postgraduate support which includes PhD student committees, thesis committees, and an annual symposium. Furthermore, as the Krause lab is part of the cell motility section of the Randall Centre you will have access to additional expertise in microscopy imaging and image analysis. Our lab owns several state of the art microscopes including high sensitivity live cell imaging, TIRF, and confocal miscroscopes. Access to more specialized advanced microscopes is provided through the Nikon Imaging Centre on our campus which will also provide in house training. More specialized training in image processing with MATLAB will be provided through a course offered by MathWorks.
As part of the cell motility section, you will also attend an internal seminar series and our lab is part of the wider London based community “The London Cell Motility Club” (https://cytoskeleton.wixsite.com/londoncellmotility) which is organized by one of the supervisors (Dr Matthias Krause), which organizes five London wide meetings a month with invited national and international speakers.
Selected relevant publications:
Carmona G, Perera U, Gillett C, Naba A, Law AL, Sharma VP, Wang J, Wyckoff J, Balsamo M, Mosis F, De Piano M, Monypenny J, Woodman N, McConnell RE, Mouneimne G, Van Hemelrijck M, Cao Y, Condeelis J, Hynes RO, Gertler FB, Krause M. (2016) Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE. Oncogene. 2016 Sep 29;35(39):5155-69.
Krause, M. and Gautreau, A. (2014) Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nature Reviews Molecular Cell Biology, 15, 577-90 (2014).
Law, A., Vehlow, A., Kotini, M., Dodgson, L., Soong, D., Theveneau, E., Bodo, C., Taylor, E., Navarro, C., Perera, U., Michael, M., Dunn, G.A., Bennett, D., Mayor, R., and Krause M. (2013) Lamellipodin and the Scar/WAVE complex cooperate to regulate cell migration in vivo. Journal of Cell Biology, 203(4), 673-689.