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

The PI3K signaling pathway is critical for normal cell function, controlling many features of cell biology and metabolism needed for cell growth and survival. The pathway is often inactive until stimulated by external growth cues, resembling insulin. Genetic mutations causing hyperactivation of this pathway are a typical feature of many cancers and drive cancer progression. One of the vital common mechanisms that drives deregulated cell growth is mutations that inactivate the tumor suppressor PTEN. In healthy cells, the PTEN enzyme turns the pathway off, and the lack of PTEN results in hyperactive PI3K signaling.

Using mouse models of prostate cancer, researchers from the Institute’s Signalling research program found that pathway hyperactivation because of lack of PTEN not only causes a sustained increase in pathway activity but in addition a dramatic rebuild of the pathway when it comes to its components and their organization. The brand new pathway architecture reduces its dependence on extracellular growth aspects and introduces a self-sustaining, positive-feedback loop meaning it might probably be energetic with minimal requirement for external cues.

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

“Surprisingly, we found that the PI3K signaling network was not simply hyperactivated but remodeled in several tumor contexts. Which means the activators of the PI3K signaling pathway in cancer are distinct to those in healthy tissue.” explained Dr Tamara Chessa, who led the study. “This means there are potential targets within the pathway which might be preferentially energetic in cancer cells, offering the chance to create drugs that concentrate on cancer cells and never healthy neighbors. Traditional, direct inhibitors of PI3Ks inhibit the PI3K pathway in each cancerous and healthy cells, limiting their advantages.”

During their research, the scientists searched for the direct activators of PI3K signaling in normal mouse prostate and prostate during which PI3K signaling had been chronically activated by lack of the tumor suppressor PTEN, resulting in the slow emergence of prostate cancer.

Of their evaluation of the tumor cells within the PTEN-lacking mice, the researchers noticed something remarkable. As expected by what is thought about PI3K pathway regulation, hyperactive PI3K signaling 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 signaling. Nevertheless, one other growth-driving mechanism, centered 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 seek out PLEKHS1, a protein with previously largely unknown function, to be a significant driver of PI3K activation and cancer growth and progression within the mouse model for prostate cancer. Not only that however the properties of PLEKHS1 are very unusual in that it’s able to each stimulating the PI3K network and being stimulated by the PI3K network, allowing positive feedback. We then wanted to seek out out if this remodeling could possibly be present in other models of cancer.” Dr Len Stephens, group leader within the Signalling research program, explains.

To explore this, the researchers examined two further models (in mice) of tumor progression driven by genetic activation of the PI3K network: a model that also slowly develops prostate cancer but is brought on by a definite style of mutation, and an ovarian tumor model. Using these models, the researchers found that PLEKHS1 doesn’t have a uniform role in remodeling PI3K networks within the absence of PTEN and that other PI3K activators may tackle more vital roles in other tissues. For instance, the researchers found that one other protein member of the PI3K signaling network, AFAP1L2, also can contribute to pathway remodeling.

Dr Phill Hawkins, group leader within the Signalling research program, is eager for the long run of this research. “Our evaluation of human datasets supports our findings within the mouse models, and strongly suggest that PI3K pathway rewiring is relevant in human cancers. We now have a possible recent avenue for therapeutic targeting of the PI3K signaling pathway in human cancers, via PLEKHS1 and potentially its upstream activating kinase, with minimal predicted toxicity.”

The findings even have vital implications for understanding of the mechanisms that cause aging. Many studies have shown that excess PI3K network activity accelerates aging and lack of PI3K activity decelerates aging however the mechanistic details are unclear. Based on this recent finding, the research team at the moment are exploring whether there may be the same but distinct rewiring event during normal aging which may result in lack of sensitivity to growth aspects like insulin and support excessive autonomous PI3K network signaling resulting in lack of normal metabolic balance and possibly the emergence of age-related inflammation.