Cancer-causing mutations rewire growth signalling in prostate cancer model

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.
• Research 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.