Cancer Mutations Growth Signaling in Prostate Cancer Model

Cell signaling experts at the Babraham Institute have discovered how prostate cancer cells proliferate without the regular growth stimuli and regulators. Understanding more about this network remodeling and the drivers of cellular development reveals molecular targets for medications to block tumor progression, which has implications for possible therapies in prostate cancer and other cancer types.

The PI3K signaling pathway is essential for normal cell function because it regulates numerous aspects of cell biology and metabolism that are required for cell growth and survival. Typically, the route is quiescent unless triggered by exogenous growth stimuli like as insulin. Many malignancies have genetic abnormalities that cause hyperactivation of this system, which drives cancer growth.

Mutations that inactivate the tumor suppressor PTEN are one of the most common pathways that induce uncontrolled cell proliferation. In healthy cells, the PTEN enzyme switches off the pathway, whereas PTEN deficiency results in hyperactive PI3K signaling.

Using mouse models of prostate cancer, researchers from the Institute’s Signaling research program discovered that pathway hyperactivation caused by PTEN loss not only results in a sustained increase in pathway activity, but also in a dramatic rebuilding of the pathway in terms of its components and organization. The new pathway architecture decreases the pathway’s reliance on extracellular growth factors and establishes a self-sustaining, positive-feedback loop, allowing it to function with little external inputs.

What was seen in the mice models’ prostate cells coincides with PI3K activity in human prostate tumors.

“Surprisingly, we found that the PI3K signaling network was not simply hyperactivated but remodeled in different tumor contexts. This means that 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 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 neighbors. Traditional, direct inhibitors of PI3Ks inhibit the PI3K pathway in both cancerous and healthy cells, limiting their benefits.”

The investigators searched for direct activators of PI3K signaling in normal mouse prostate and prostate where PI3K signaling has been chronically elevated by loss of the tumor suppressor PTEN, resulting in the slow onset of prostate cancer.

The researchers discovered something remarkable while studying tumor cells in PTEN-deficient mice. According to what is known about the PI3K pathway, overactive PI3K signaling activated a negative feedback mechanism that suppressed pathway activation by growth factor signals.

As expected, this negative feedback loop kicked in and shut down normal growth factor-driven PI3K signaling. However, another growth-promoting pathway, focusing on a previously unknown protein termed PLEKHS1, was discovered. This feedback has no effect on PLEKHS1, which forms a self-sustaining positive feedback loop that drives growth. This is a significant milestone in the course of prostate cancer.

“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 remodeling could be found in other models of cancer,” Dr. Len Stephens, group leader in the Signaling research program, explains.

To investigate this further, the researchers looked at two additional models (in mice) of tumor progression driven by genetic activation of the PI3K network: one that slowly develops prostate cancer but is caused by a different sort of mutation, and one that develops ovarian cancer. Using these models, the researchers discovered that in the absence of PTEN, PLEKHS1 does not play a uniform role in redesigning PI3K networks, and that alternative PI3K activators may play more essential roles in various tissues.

The researchers discovered, for example, that another protein member of the PI3K signaling network, AFAP1L2, can also contribute to pathway remodeling.

Dr. Phill Hawkins, group leader in the Signaling research program, 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 signaling pathway in human cancers, via PLEKHS1 and potentially its upstream activating kinase, with minimal predicted toxicity.

The findings are also significant for understanding the mechanisms that cause aging. Many studies have indicated that increased PI3K network activity promotes aging and decreased PI3K activity slows aging, although the underlying mechanisms are unknown.

Based on this recent discovery, the researchers are now investigating whether there is a similar but distinct rewiring event during normal aging that may lead to loss of sensitivity to growth factors such as insulin and support excessive autonomous PI3K network signaling, resulting in loss of normal metabolic balance and possibly the emergence of age-related inflammation.

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