The best laid plans of mice in men

Scientists from the UK and Australia have created a mouse strain that expresses a fluorescing biosensor in every cell of its body, allowing diseased cells and drugs to be tracked and evaluated in real time.

The study, which has been published in the journal Cell Reports, was begun by Dr Paul Timpson at the Beatson Institute for Cancer Research in Glasgow and completed at Sydney’s Garvan Institute of Medical Research. He collaborated throughout the process with Dr Heidi Welch from the Babraham Institute in Cambridge, the creator of the mouse.

The biosensor is a single molecule probe named ‘Raichu-Rac’ and was invented by Japanese scientist Professor Miki Matsuda in 2002. It mimics the action of a target molecule, in this case a protein known as ‘Rac’, which drives cell movement in many types of cancer. The researchers’ mouse strain, Rac-FRET, ubiquitously expresses the Raichu-Rac biosensor.

Rac behaves like a switch, oscillating on the molecular level between two states - active or inactive. When Rac is active, the biosensor picks up chemical cues and glows blue. When Rac is inactive, the biosensor glows yellow. Dr Timpson explained, “In cancers, a lot of blue indicates an aggressive tumour that is in the process of spreading.”

Breast tumour - blue regions show high Rac activity, meaning the tumour is likely to spread.

Using sophisticated imaging techniques, it is possible to follow Rac activation in any organ at any time, or watch moment-by-moment oscillation of Rac activity at the front or back of cells as they move in the body. The researchers can therefore follow where Rac is driving invasion, noted Dr Timpson.

“We monitored Rac activity in normal or disease states of intestinal, liver, mammary, pancreatic and skin tissue, in response to stimulation or inhibition and upon genetic manipulation of upstream regulators, revealing unexpected insights into Rac signalling during disease development,” the researchers said.

The technology has also been used to monitor Rac activity in response to drug treatment. According to Dr Timpson, “You can literally watch parts of a tumour turn from blue to yellow as a drug hits its target. This can be an hour or more after the drug is administered, and the effect can wane quickly or slowly. Drug companies need to know these details - specifically how much, how often and how long to administer drugs.”

The researchers added that the mouse “enables FRET imaging and quantification of Rac activity in live tissues and primary cells without affecting cell properties and responses”. This is the first time a mouse has been genetically modified successfully to express the molecule throughout the body without affecting cell function.

The mouse can be used to study any cancer type by crossing it with other models, limiting expression of Raichu-Rac to specific cell or tissue types. It can also be adapted to study diseases other than cancer by expressing the biosensor in different disease models, providing the potential for looking at a broad range of diseases and molecular targets, said Dr Timpson.

Dr Welch believes the mouse will help other scientists to understand Rac and work out how to stop cancer cells from moving. She credits Professor Matsuda for his original invention and the part he played in the most recent study.

“Miki Matsuda was super-helpful in suggesting the expression levels we should be looking for, and in recommending the exact biosensor we should use, out of many he developed,” she said.

Competition is growing rapidly in this area, said Dr Welch, with Professor Matsuda himself making biosensor mice for a variety of target molecules.

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