Lipid based signal transduction mechanisms and their roles in cancer

Research

My group (visit the website here) studies the lipid phosphatase, PTEN, one of the most frequently lost tumour suppressors in human cancers. Our research aims to understand the mechanisms by which PTEN mediates its effects, esecially in terms of its lipid and potentially protein substrates. We also study mechanisms by which PTEN activity is controlled.

In this work, we focus especially on two tumour types, glioblastoma and breast cancer, in which PTEN mutation is particularly common and we use a range of techniques from lipid biochemistry and proteomics to work on cultured cell systems and in vivo.

The regulation of the tumour suppressor phosphatase, PTEN

PTEN is a lipid phosphatase that acts to suppress the PI 3-kinase signalling pathway, the incorrect regulation of which is a cause of diseases including diabetes and many cancers. Indeed, tens of thousands of tumours are diagnosed in the UK each year that have lost PTEN tumour suppressor activity. Despite this pathological significance, relatively little is known about the mechanisms controlling the function of PTEN. We are currently studying several mechanisms of PTEN regulation, including phosphorylation, oxidation and ubiquitination.

PTEN and epithelial tissue architecture

Multicellular organisms require their cells to communicate and assemble cooperatively into the correct tissue structures. Conversely, the development of almost all solid tumours is accompanied by a loss of tissue architecture, and in some cases this loss of structure appears to be a central process driving tumour growth, rather than its by-product. Experimentally these events can be studied using 3D cell culture techniques in which epithelial cells can be induced to form both hollow cysts and tubules.

For some years our lab has been studying PTEN, which is a lipid phosphatase and important tumour suppressor. PTEN controls many important cellular processes, such as growth, proliferation, survival and motility, by inhibiting PI 3-kinase dependent signalling. Knocking down PTEN expression in 3D culture by interfering RNA has dramatic effects on cell proliferation and tissue morphology that are not evident in standard 2D culture. A project is available to investigate these effects, addressing cell signalling events, and cell polarity and architecture in this system. Within this work, efforts will be put into identifying PTEN binding proteins involved in controlling and localising PTEN within these polarised cells.

Images are shown of a canine kidney epithelial cell line with the cell junctional protein beta-catenin shown in green and DNA shown in blue. The cells in (A) express normal PTEN protein and in (B), PTEN expression has been knocked down using RNA interference. Similar results are obtained using NMuMG breast epithelial cells.

We work within the well resourced Inositol Lipid Signalling Laboratory, part of the Division of Molecular Physiology in the new James Black Centre

Our research is funded by the Medical Research Council and the Association for International Cancer Research

Informal enquiries about posts within the group can be made by email to n.r.leslie@dundee.ac.uk.

Publications

1. Leslie NR et al, (2007). PtdIns(3,4,5)P3-dependent and –independent roles for PTEN in the control of cell migration. Curr. Biol., 17, 115-125
2. Leslie NR et al, (2008). Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene, 27, 5464-5476
3. Maccario H et al, (2010). Ubiquitination of PTEN inhibits phosphatase activity and is enhanced by membrane targeting and hyperosmotic stress. J Biol Chem. 285, p12620-12628
4. Davidson L et al, (2010). Suppression of cellular proliferation and invasion by the concerted lipid and protein phosphatase activities of PTEN. Oncogene 29, 687-97
5. Leslie NR and Foti, M (2011). Non-genomic loss of PTEN function is cancer: not in my genes. Trends Pharmacol. Sci. epub 12/1/2011