New fundamental biology may aid cancer treatments

New research represents a promising step towards better understanding of a key cancer gene. A long-running collaboration between researchers at the Babraham Institute, Cambridge and the AstraZeneca IMED Biotech Unit reveals new insights into how the PTEN gene may control cell growth and behaviour and how its loss contributes to the development and advancement of certain cancers.

PTEN is reportedly the second most commonly altered gene in human cancers. The study, led by Dr Len Stephens and Dr Phill Hawkins and published today in the journal Molecular Cell, reveals why loss of the PTEN gene has such an impact on many people with prostate cancer, as well as in some breast cancers. These results, which also include work from Akita University, Japan, and contributions from GSK could help to identify patients likely to benefit from novel targeted therapies.

PTEN is known as a tumour suppressor gene meaning that it typically slows the growth of cells and its loss can lead to cancer. By regulating the levels of the chemical phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P₃), PTEN helps to limit cell growth and so prevents cancer.

Yet, the new paper shows that this is only part of the story. The team at the Institute, supported by GSK and together with AstraZeneca have identified another way that PTEN may prevent uncontrolled cell growth. PTEN can also reduce the levels of another similar molecule known as phosphatidylinositol-3,4-bisphosphate (PI(3,4)P₂). The role of PI(3,4)P₂ is still becoming clear but it may be able to alter the activity of the AKT protein, a key regulator of cell growth. PI(3,4)P₂ may also influence several other proteins that regulate the process of invasion; how cancer cells spread and move through the body.

Speaking about the research, Dr Hawkins said: “We were really surprised that loss of PTEN caused such a dramatic increase in PI(3,4)P₂ in our mouse model of prostate cancer. PI(3,4)P₂ has generally been a bit of an enigma and many thought it was just a by-product of PI(3,4,5)P₃. Our work suggests that studying PI(3,4)P₂-regulated processes may reveal why PTEN is such a powerful tumour suppressor and may also help us to identify new therapeutic targets in PTEN-mutated cancers.”

“Over 40% of prostate cancers lose PTEN and some lose both PTEN and another tumour suppressor gene, INPP4B, but we didn’t previously have a clear picture of how this affects tumour growth,” says IMED Biotech Unit scientist Sabina Cosulich, at AstraZeneca. “The new discovery has given us an important link between the biochemical function of PTEN and its role in prostate cancer, and in some triple negative breast tumours for which treatment is currently limited.”

By studying human cancer cells and animal models of cancer in the lab, our researchers have shown that loss of PTEN leads to high levels of PI(3,4)P₂, which could result in hyperactivation of AKT. This may indicate AKT as an effective target for new cancer treatments. AstraZeneca’s AKT inhibitor is currently in clinical trials for prostate, breast and other cancers. This collaboration could help to devise tests to identify patients who will benefit from these targeted therapies.

Dr Cosulich concludes: “Having such an open collaboration was essential for addressing a scientific puzzle of great significance to cancer research. Our team members are in regular contact and frequently work alongside each other. Hearing about the lipid biochemistry research from the Babraham Institute team and realising how we could translate its potential from an oncology perspective was a great moment for all of us!”

Notes to Editors:

Publication Reference
Malek, Mouhannad et al.: "PTEN regulates PI(3,4)P2 signalling downstream of Class I PI3K", Molecular Cell, Oct 2017.
DOI: 10.1016/j.molcel.2017.09.024

Research Funding
This research was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) through an Institute Strategic Programme Grant for Cell Signalling, AstraZeneca, the Wellcome Trust, GSK and the Japan Agency for Medical Research and Development.

Press Contact
Dr Jonathan Lawson, Babraham Institute Communications Manager jonathan.lawson@babraham.ac.uk

Image Credit
Credit: A. Kielkowska and adapted by T. Chessa
PI(3,4)P₂: a new marker for tumour progression
PTEN is a well-known tumour suppressor, its function being the prevention of the cells in our body becoming cancerous. In fact, many human cancers are characterised by mutations or deletions in this tumour suppressor. Our work has shown a new function for PTEN, namely the ‘destruction’ of a signalling molecule called PI(3,4)P₂. PI(3,4)P₂ levels in the prostate correlate with early-stage tumour growth and later-stage tumour progression towards metastasis, pointing to PI(3,4)P₂ being a key signalling molecule in cancer.
 
Shown here is an image of a mouse prostate lacking PTEN (and INPP4B – another tumour suppressor that does not affect levels of PI(3,4)P₂ in mouse prostate) in epithelial cells – these are the cells lining the ducts in the prostate. The image was captured at an early stage of tumour progression. At this stage of tumour progression, most of the ducts appear normal/hollow (grey cells). However, a proportion of ducts display early stages of tumour growth – these contain high levels of PI(3,4)P₂ (red, orange and yellow cells), especially at the tips of the ducts, which contain the fastest growing cells (cells appear ‘on fire’). This image highlights the key findings of our work: that PTEN directly ‘destroys’ PI(3,4)P₂ and that PI(3,4)P₂ is a marker for tumour growth and progression.

Affiliated Authors (in author order):
Mouhannad Malek, Anna Kielkowska, Tamara Chessa, Karen Anderson, David Barneda, Pinar Pir, Véronique Juvin, Vladimir Kiselev, Izabella Niewczas, Alexandre Valayer, Dominik Spensberger, Marine Imbert, Jonathan Clark - Signalling Programme, Babraham Institute, Nicolas Le Novère, Phillip T Hawkins - Group Leader, Signalling Programme, Babraham Institute, Len R Stephens - Group Leader, Signalling Programme, Babraham Institute

Animal Statement:
The use of animals in this study was performed in accordance with the Babraham Institute’s Animal Welfare and Ethical Review Body (AWERB) and the Animals in Science Regulation Unit (ASRU) of the UK Home Office, with all protocols approved and detailed under Home Office Project Licence 70/8100. The study used male C57BL6J mice. Mice were housed in the Biological Support Unit at the Babraham Institute under specific pathogen-free conditions.

Multiple independent experiments were carried out using several biological replicates specified in the legends to figures. In accordance with the 3Rs, we used a minimum number of mice per experiment (typically n=3 per genotype per experiment). Mice were checked daily by qualified technicians and were healthy throughout the duration of the study. At the ages of 10-16 weeks tissue samples were collected. Mice lacking PTEN in this study do not develop prostate adenocarcinoma (‘prostate cancer’) before the age of 6 months, hence, mice used in this study are in a very early pre-cancerous stage that would not currently be clinically diagnosed.

Mice were monitored at least twice per day and appeared healthy and active. Environment enrichment was provided (e.g. tunnels, elevated rafts) as well as food treats and nesting material. In the major part of the study, alternatives to animal models (cell lines and human material; mathematical modelling) were used. Importantly, mice were used for the sole purpose of providing an in vivo relevance to the findings reported in the study.

Please follow the link for further details of the Institute’s animal research and our animal welfare practices: http://www.babraham.ac.uk/about-us/animal-research

About the Babraham Institute:
The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) to undertake world-class life sciences research. Its goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing.