PhD Research Project: The role of PICK1 in astrocytic tumour invasion.

United Kingdom
Oct 18, 2016
Jan 18, 2017
Organization Type
University and College
Full Time
Astrocytoma is the most common form of brain cancer with characteristic widespread tumour invasion throughout the CNS; patients have a poor prognosis. Actin dynamics are involved in cell migration and invasion, and also in the regulation of vesicle trafficking, which can indirectly influence cell motility by regulating the subcellular localisation of specific proteins. PICK1 inhibits Arp2/3-mediated actin polymerisation and regulates the trafficking of various cell surface proteins. We have found that PICK1 expression is downregulated in astrocytoma cell lines and in human brain tumours, and also that exogenously increasing PICK1 expression inhibits astrocytoma cell invasion through a 3D matrix, indicating that reduced PICK1 contributes to astrocytoma invasion. Critical outstanding questions are:

1) how does loss of PICK1 affect astrocytoma migration and invasion?

2) what is the effect of PICK1 manipulation on tumour progression in vivo?

We have identified candidate cell surface proteins that may be aberrantly trafficked in astrocytoma cell lines based on their known interaction with PICK1 and role in astrocytoma invasion. Proteomics will be used to identify further proteins. Live and fixed-cell imaging will define the details of altered trafficking in astrocytoma lines. In addition, the hypothesis that PICK1 has direct effects on the cytoskeleton to regulate cell invasion will be tested by analysing PICK1 mutants that block trafficking, but maintain Arp2/3 inhibition. To investigate the effect of altered PICK1 expression in vivo, astrocytoma cells stably expressing PICK1 or mutants following lentiviral transduction will be injected into immunodeficient rats, and tumour progression compared across conditions. In addition, state-of-the-art convection-enhanced drug delivery systems (CED) will be used to apply pharmacological agents that either directly modulate surface protein activity, or regulate relevant trafficking events defined by the in vitro work. CED employs fine catheters implanted into the brain, which very accurately administer drugs directly to the brain extracellular space in concentrations that would result in significant toxicity if given systemically.

This project will translate basic cell biology into a clinically relevant animal model for astrocytic tumours, and will investigate novel approaches to reducing tumour progression in vivo. The cell biology and imaging expertise in Jon Hanley’s lab provides the perfect environment for training in these techniques. Ali Bienemann will personally pass on her expertise in CED, lab to clinic translation and in vivo techniques, providing the student with excellent training to progress the project to its full potential.

This is a collaborative project between Dr Jon Hanley and Dr Alison Bienemann (Clinical Sciences, University of Bristol)

Funding Notes

Further details and online application: View Website