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Cancer-causing mutations transform the architecture of a key growth-promoting signalling pathway

Key points: 

• The PIP3/PI3K signalling pathway is one of the most important signalling mechanisms in our cells, affecting cell metabolism and growth. It is also one of the most frequently altered pathways in human cancer.
• 51���� from the Institute has shown that PI3K pathway remodelling is a common feature of cancers driven by hyperactivated PI3K signalling. Working in prostate tumour models the team identified an unknown activator driving PI3K signalling and cancer growth in a way that is released both from needing positive growth signals and also from growth-limiting feedback controls.
• This knowledge identifies new components of the PI3K signalling network that represent potential vulnerabilities and targets for drug development to keep cancer cell growth in check. 
• Vitally, the protein identified in the rewired signalling network has no apparent role in healthy prostate tissue, and is thought to only drive cell growth specifically in tumour tissue.

Experts in cell signalling at the Babraham Institute have identified how prostate cancer cells achieve cell growth free from the usual growth cues and regulators. This discovery has implications for potential therapeutics in prostate cancer and other cancer types as understanding more about this network remodelling and the drivers of cellular growth provides molecular targets for drugs to stop tumour progression.

The PI3K signalling pathway is critical for normal cell function, controlling many aspects of cell biology and metabolism needed for cell growth and survival. The pathway is typically inactive until stimulated by external growth cues, such as insulin. Genetic mutations causing hyperactivation of this pathway are a common feature of many cancers and drive cancer progression. One of the most common mechanisms that drives deregulated cell growth is mutations that inactivate the tumour suppressor PTEN. In healthy cells, the PTEN enzyme turns the pathway off, and the loss of PTEN leads to hyperactive PI3K signalling. 

Using mouse models of prostate cancer, researchers from the Institute’s Signalling research programme found that pathway hyperactivation due to loss of PTEN not only causes a sustained increase in pathway activity but also a dramatic rebuild of the pathway in terms of its components and their organisation. The new pathway architecture reduces its dependence on extracellular growth factors and introduces a self-sustaining, positive-feedback loop that means it can be active with minimal requirement for external cues.

Importantly, what was seen in the prostate cells from the mouse models correlates with PI3K activity in human prostate cancers.

“Surprisingly, we found that the PI3K signalling network was not simply hyperactivated but remodelled in different tumour contexts. This means that the activators of the PI3K signalling pathway in cancer are distinct to those in healthy tissue.” explained Dr Tamara Chessa, who led the study. “This suggests there are potential targets in the pathway that are preferentially active in cancer cells, offering the opportunity to create drugs that target cancer cells and not healthy neighbours. Traditional, direct inhibitors of PI3Ks inhibit the PI3K pathway in both cancerous and healthy cells, limiting their benefits.”

During their research, the scientists looked for the direct activators of PI3K signalling in normal mouse prostate and prostate in which PI3K signalling had been chronically activated by loss of the tumour suppressor PTEN, leading to the slow emergence of prostate cancer.

In their analysis of the tumour cells in the PTEN-lacking mice, the researchers noticed something remarkable. As expected by what is known about PI3K pathway regulation, hyperactive PI3K signalling triggered a negative feedback mechanism to suppress pathway activation by growth factor signals. This negative feedback mechanism kicked in as expected and shut down normal growth factor driven activation of PI3K signalling. However, another growth-driving mechanism, centred around a virtually unstudied protein called PLEKHS1, was identified. PLEKHS1 is unaffected by this feedback and creates a self-sustaining positive-feedback loop driving growth. This represents a key event in prostate cancer progression.

“We were surprised to find PLEKHS1, a protein with previously largely unknown function, to be a major driver of PI3K activation and cancer growth and progression in the mouse model for prostate cancer. Not only that but the properties of PLEKHS1 are very unusual in that it is capable of both stimulating the PI3K network and being stimulated by the PI3K network, allowing positive feedback. We then wanted to find out if this remodelling could be found in other models of cancer.” Dr Len Stephens, group leader in the Signalling research programme, explains. 

To explore this, the researchers examined two further models (in mice) of tumour progression driven by genetic activation of the PI3K network: a model that also slowly develops prostate cancer but is caused by a distinct type of mutation, and an ovarian tumour model. Using these models, the researchers found that PLEKHS1 does not have a uniform role in remodelling PI3K networks in the absence of PTEN and that other PI3K activators may take on more important roles in other tissues. For example, the researchers found that another protein member of the PI3K signalling network, AFAP1L2, can also contribute to pathway remodelling.

Dr Phill Hawkins, group leader in the Signalling research programme, is hopeful for the future of this research. “Our analysis of human datasets supports our findings in the mouse models, and strongly suggest that PI3K pathway rewiring is relevant in human cancers. We now have a potential new avenue for therapeutic targeting of the PI3K signalling pathway in human cancers, via PLEKHS1 and potentially its upstream activating kinase, with minimal predicted toxicity.” 

The findings also have important implications for understanding of the mechanisms that cause ageing. Many studies have shown that excess PI3K network activity accelerates ageing and loss of PI3K activity decelerates ageing but the mechanistic details are unclear. Based on this recent finding, the research team are now exploring whether there is a similar but distinct rewiring event during normal ageing that might lead to loss of sensitivity to growth factors like insulin and support excessive autonomous PI3K network signalling leading to loss of normal metabolic balance and possibly the emergence of age-related inflammation.

Notes to Editors

Publication reference

Chessa, T. A.M., et al, PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate, Molecular Cell, DOI:  

Press contact

Honor Pollard, Communications Officer, honor.pollard@babraham.ac.uk

Image description

A section of a painting by lead researcher, Tamara Chessa, representing the research findings described in Chessa et al. PI3K signalling is represented as an electric circuit, with the nodes representing proteins. In PTEN-null tumours, a decrease in signalling to PI3K (depicted in yellow) is represented by blue wires. PLEKHS1, depicted in red, becomes the dominant driver of PI3K signalling and tumour progression in PTEN-null tissue.

Affiliated authors (in author order):

Tamara Chessa, senior post doc researcher, Hawkins-Stephens lab

Piotr Jung, postdoctoral fellow, Hawkins-Stephens lab

Arqum Anwar, PhD student, Hawkins-Stephens lab

Sabine Suire, senior research associate, Hawkins-Stephens lab

Karen Anderson, senior research associate, Hawkins-Stephens lab

David Barneda, postdoctoral researcher, Hawkins-Stephens lab

Anna Kielkowska, former PhD student, Hawkins-Stephens lab

Barzan Sadiq, former PhD student, Hawkins-Stephens lab

Ieng Wai Lai, former visiting student, Hawkins-Stephens lab

David Oxley, Head of the Mass Spectrometry facility

Dominik Spensberger, former head of the Gene Targeting facility

Anne Segonds-Pichon, former biostatistician, Bioinformatics facility

Michael Wilson, strategic fellow, Hawkins-Stephens lab

Simon Walker, Head of the Imaging facility

Hanneke Okkenhaug, deputy manager, Imaging facility

Phillip Hawkins, senior group leader, Signalling programme

Len Stephens, senior group leader, Signalling programme

51���� funding

The work was supported by grants from the BBSRC and the MRC - both part of UKRI, an ITN PhD studentship to Piotr Jung, CRUK Cambridge Centre PhD funding to Arqum Anwar and a grant to support research translation from the KEC programme at the Babraham Institute.

Animal research statement

As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research used mice in breeding protocols to generate genetically modified mice. These mice were created to allow the function of different components of the PI3K pathway to be explored. Some mice were given inhibitors of PI3K. Mice were humanely killed for access to tissue samples taken from prostates from male mice and ovaries from female mice.

All animal experiments at the Babraham Institute were reviewed and approved by the Institute’s Animal Welfare and Ethics Review Body and performed under Home Office Project license PPL 70/8100.

Please follow the link for further details of our animal research and our animal welfare practices.

About the Babraham Institute

The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular 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. The Institute is strategically funded by the Biotechnology and Biological Sciences 51���� Council (BBSRC), part of UK 51���� and Innovation, through Institute Strategic Programme Grants and an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.

About BBSRC

The Biotechnology and Biological Sciences 51���� Council (BBSRC) is part of UK 51���� and Innovation, a non-departmental public body funded by a grant-in-aid from the UK government.

BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

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