New research overturns decades of thinking on how Epidermal Growth Factor Receptor (EGFR) signals
02 Nov 2016
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Four decades of thinking on signal transduction has been overturned thanks to a research project involving contributions from scientists and engineers in the UK.

 

​​​The foreground shows a model of the EGFR tetramer. In the background there is a single molecule image of EGFR in cancer cells; each bright spot is an individual EGFR molecule, or a small cluster of molecules

 
​It is hoped that a new method, developed by scientists working at the Science and Technology Facilities Council’s Central Laser Facility (CLF) in Oxfordshire, could be used to test the effect and efficacy of new drugs and to understand better the differences between patients that currently can lead to varying responses to treatment.

The research is featured in a paper published in Nature Communications that describes the use of a technique developed at the CLF’s Octopus facility to map out the structure of molecular complexes in cell membranes, with a resolution of 5 nm, that is twice the width of a strand of human DNA. The data from these experiments has been used in combination with powerful molecular modelling techniques to provide important new information about the role of complex formation in the process of signalling by the Epidermal Growth Factor Receptor (EGFR).

The Epidermal Growth Factor Receptor (EGFR) family is a group of “gatekeeper” molecules that act as switches controlling the growth of cells. When the switching mechanism goes wrong, cells can be triggered to divide uncontrollably, resulting in cancer. Because of this the EGFR molecule is the focus of a number of anti-cancer therapies.

Prof. Marisa Martin-Fernandez, head of the CLF’s Octopus facility in the Research Complex at Harwell said that “To develop more effective drugs and understand the mechanisms of drug resistance and patient to patient variability, we need to understand how the signalling mechanism works. The team from the CLF have developed a method that can show the “fingerprint” of the clusters with unprecedented resolution”.

Many of the latest anti-cancer drug therapies adopt a targeted approach, aimed at blocking the faulty switches, rather than the “sledgehammer” approach of conventional chemotherapy that targets all growing cells. These targeted drugs have the potential to provide much more effective treatments with fewer side effects, and already many of them are showing benefits in terms of extension of high quality lifespan for patients with previously unresponsive cancers.

However, the goal of a complete cure remains elusive, due to problems like the development of resistance to the drugs, and the variation of responses from patient to patient.

For a long time scientists have thought that two individual EGFR molecules come together when they interact with a small signalling molecule. When the molecules come together, the signal is switched on. However, in recent years a more complex picture has emerged, with hints that EGFR is often present in assemblies of more than two molecules. Understanding the significance of these larger molecular clusters has been hampered by the lack of a method that can probe the structure of the clusters in cells.

The CLF team used their Octopus advanced imaging facility to show that clustering is vitally important in the signalling process, and that cancer-causing mutations of the molecules change the “fingerprint” of these clusters. The results are published in Nature Communications today.

The STFC team worked with scientists using the world’s most powerful molecular simulations computer, at D.E. Shaw Research in New York, allowing them to build a detailed model of how the receptor molecules work in cells. It is hoped that the method can now be used to test the effect of new drugs and to understand differences between patients that cause varying responses to treatment.

The work has been funded by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC) and there was also involvement from the Francis Crick Institute and King’s College London, Swinburne University (Melbourne, Australia) and Washington University School of Medicine (St Louis, Missouri, USA).

Link to Nature Communications article: EGFR oligomerization organizes kinase-active dimers into competent signalling platforms (link opens in a new window)

CLF Contact: Prof. Marisa Martin-Fernandez

The Octopus advanced imaging cluster: Further information

Contact: Martin-Fernandez, Marisa (STFC,RAL,CLF)