New technique to delve further into cancer cell biology

A team of researchers from Garvan and UNSW Australia has developed a new technique that helps to unravel some of the complexities of how proteins interact with each other in breast cancer and other diseases.

BiCAP reveals new networks in breast cancer

20 July 2016

Our cells each contain thousands of proteins, which together carry out much of the work of the cell. To understand how proteins work – whether in diseased or healthy cells – we need to grasp which proteins connect with which, when these partnerships occur, and what happens in the cell as a result.

In a paper published last week in Science Signaling, an international team of scientists led by Dr David Croucher (Garvan Institute of Medical Research) and Dr Darren Saunders (UNSW Australia) describe a new technique, called BiCAP, that will help scientists paint a more nuanced picture of protein-protein interactions than has previously been possible.

The researchers have been studying a protein called ERBB2, which is also known as HER2 and is the driver of the particularly aggressive HER2-positive subset of breast cancers. HER2 is known to promote tumour progression by helping to keep cancer cells alive.

“The ability to really understand how HER2 signals in the cell is very important,” says Dr Croucher. “We know that HER2 can partner with several other proteins in the cell.

“HER2 partnerships change when cells are treated with anticancer therapies, and change even further when cells become resistant to therapy – which, unfortunately, is very common in this type of breast cancer.

“We’ve used our new technique – called Bimolecular Complementation Affinity Purification, or BiCAP for short – to shed light on which proteins partner with HER2.

“So, when HER2-positive cancers become resistant to therapy, for instance, we can look to see if the protein partnering has changed. That means that, even if those resistant cells have the same amount of HER2 protein as in the original tumours, we can get a clearer sense of how the ‘behaviour’ of HER2 is actually changing in terms of which other proteins HER2 partners with – and how those changes might help the cells resist anticancer therapies.”

The new technique makes it possible to look directly at any two protein partners and how their interaction impacts on the cell. This is a big step forward from previous technology, which allowed scientists to only look at one protein and how it partnered, regardless of changing cellular contexts.

BiCAP uses nanotechnology and an engineered antibody or “nanobody” designed to recognise specific protein fragments when two proteins are bound together.  By combining BiCAP with another method called proteomics in this study, the scientists were able to produce a map of all the HER2 binding partners and signalling networks in these types of cells – “a bit like a giant subway map”, as Dr Saunders puts it.

Dr Croucher says the BiCAP technology has widespread potential application in medical research.

“We’re looking forward to using BiCAP to help us understand drug resistance in other types of cancer and in the future are aiming to apply it to other human diseases.”

This research was performed with collaborators in Ireland and Canada and was funded by Cancer Institute NSW, the National Health and Medical Research Council, Science Foundation Ireland, the NSW Office of Science and Medical Research, a Guest Family Fellowship, and the Mostyn Family Foundation.

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