Melbourne scientists have for the first time filmed the process which determines how big our organs grow, yielding new insights into the “Hippo pathway”. A better understanding of this long-preserved mechanism – which has changed little through time and is seen across species – may help to develop new therapeutics for the treatment of cancer.
The research, led by Professor Kieran Harvey, is published in the journal Current Biology.
“The findings are highly significant because they provide a whole new level of understanding of how this key organ size control pathway works,” says Professor Harvey, who has a dual appointment at the Peter MacCallum Cancer Centre and Monash Biomedicine Discovery Institute (BDI).
First author on the paper, Dr Sam Manning, is a postdoctoral Research Fellow who helped Professor Harvey establish his laboratory at the Monash BDI.
Although it controls other functions, the Hippo pathway’s primary role is to determine organ size. Cancers including melanoma and mesothelioma can develop when the process goes awry and cells grow uncontrolled.
“Understanding how the output of signalling pathways are finely tuned is vital in determining how they become deregulated in cancer,” Dr Manning said.
Professor Harvey said the use of live imaging to investigate the pathway – a first for the field – enabled the scientists to closely examine a main player in the process, a transcription factor (protein) called Yorkie, through which all information relayed as part of Hippo is funnelled.
“We made ‘movies’ and watched Yorkie move in and out of the cell nucleus as organs grew,” Professor Harvey said.
“You miss a lot of information if you investigate this through fixed images, as has been done in the past – it’s like only seeing one frame of a movie,” he said.
The movies were made by attaching a microscope lens to the back of a Drosophila fly to watch specific organs as they grew – something not attempted previously in research into the Hippo pathway, Professor Harvey said.
This allowed the researchers to make two new observations: that Yorkie bound strongly to DNA during mitosis (when cells split in two); and that it shuttled constantly between the nucleus and cytoplasm rather than sitting static in the cytoplasm waiting for a signal to move into the nucleus.
“From this we can say the Hippo pathway acts more like a dimmer switch than an on/off switch to control Yorkie activity,” Professor Harvey said.
“By studying live organs as opposed to isolated cells in culture, we have shown how Hippo signalling can be tuned across a tissue – by regulating the rate at which the key downstream component, Yorkie, is able to access the nucleus and DNA. This will help us understand how YAP – the human equivalent of Yorkie – becomes hyper-activated to drive cancer,” Dr Manning said.
Professor Harvey said the findings could apply to other functions controlled by Hippo, such as cell fate – whether a new cell becomes one type of cell or another.
The pathway, conserved for millions of years, was first discovered in the Drosophila fly, in which most of the important insights have been made since.
“Drosophila provide a roadmap of what we should be doing in other species and how the pathway works in humans,” Professor Harvey said.
“I predict that other groups will now look at what we found in mammals such as mice,” he said.
This research was funded by the Australian National Health and Medical Research Council and the CASS Foundation.
Read the paper titled "Dynamic fluctuations in subcellular localization of the Hippo pathway effector Yorkie in Vivo".