
Scientists from the university of Dundee have developed novel approaches to peek inside cells and map exactly how one of the most common cancer genes perturbs biochemical signal transfer. This discovery and the associated technological innovations are now published in EMBO Molecular Systems Biology and underpin a prospective future research programme led by Dr Madsen within the MRC Protein Phosphorylation and Ubiquitylation Unit.
Much like the reliance of human society on high-precision digital communication networks, the function of the human body depends on the ability of cells to transmit biochemical information with high fidelity. This is enabled by complex circuits made up of small molecules like proteins. One such protein, known as PIK3CA, is a master regulator of the ability of our cells to sense and respond to a wide range of signals, most notably those involved in growth and metabolic regulation - for example, the hormone insulin.
Human cancers hijack the PIK3CA protein for enhanced growth, survival and metastatic spread. They do so through genetic changes that result in a hyperactive version of the molecule. The most common of these changes, known by the somewhat cryptic name H1047R, was long thought to act as a simple but powerful ON switch of PIK3CA and the biochemical circuit that it controls. The prevailing picture was therefore that PIK3CA H1047R was no longer responsive to external signals - it was simply ON all the time. Accordingly, switching PIK3CA off by pharmacological means has been at the centre of major drug development efforts nationally and internationally.
Yet, already as a PhD student at University of Cambridge, Dr. Madsen discovered that cells really cared about how much PIK3CA H1047R they have inside them. Simply doubling its dose led to dramatically different cell behaviour which was unexpected for what was otherwise considered to be a simple, binary ON switch. How then does it work? Supported by a prestigious Sir Henry Wellcome Postdoctoral Fellowship, Dr. Madsen set out to address this exact question during a 4-year journey that started in December 2020 at University College London Cancer Institute in Prof. Bart Vanhaesebroeck’s research group and finished at University of Dundee (where Dr. Madsen now leads an independent research group).
The journey started with the need for technological innovation as Dr. Madsen and the team had to find a way to measure the exact amount of information that cells transmit through PIK3CA when they are faced with different external signals. They succeeded through the use of so-called single-cell assays that allow accurate measurements of biochemical activity at different levels of the circuit controlled by PIK3CA. The high precision of the results allowed the Team to apply mathematical calculations that are commonly used in studies of digital communication systems. Comparing the fidelity of information transfer in cells with normal PIK3CA, to those with PIK3CA H1047R, Dr. Madsen and Team discovered that PIK3CA H1047R is not a binary ON switch but rather a sophisticated modifier of signal transfer fidelity. They found that cells would still respond to external signals, however much like a person with blurred vision, cells with PIK3CA H1047R were no longer able to distinguish these signals from one another accurately, causing aberrant cellular responses to take place.
This blurring of signal transfer had its origin in the ability of PIK3CA H1047R to amplify responses from signals that would normally not rely on PIK3CA for efficient information transfer. This now opens for studies that seek to identify smarter ways of targeting PIK3CA in cancer and other diseases. Dr. Madsen says: “This discovery and the new tools that we have developed are enabling new opportunities for us to identify smarter and more specific ways of targeting abnormal PIK3CA, for example, by focusing on the biochemical connections that are amplified selectively whilst leaving essential functions of this protein intact. Excitingly, our technologies have also put us in a position to address an overlooked feature of cells with PIK3CA H1047R, namely their incredible ability to sample a wide range of functional behaviours which contributes to their evasive responses to existing therapies.”
Earlier this year, Dr. Madsen was awarded a £1.8 million UKRI Future Leaders Fellowship which will enable her group to follow up on the above discoveries and focus on the development of so-called “state-gating therapeutic approaches” for systems with aberrant PIK3CA function.