February 18, 2013
February 18, 2013 , New York, NY and Melbourne, Australia - A Melbourne-based research team has discovered a genetic defect that can halt cell growth and force cells into a death-evading survival state. The finding has revealed an important mechanism controlling the growth of rapidly-dividing cells that may ultimately lead to the development of new treatments for diseases including cancer.
The discovery was made by Associate Professor Joan Heath, Dr Yeliz Boglev and colleagues at the Melbourne-Parkville Branch of the Ludwig Institute for Cancer Research. Dr Kate Hannan, Associate Professor Rick Pearson and Associate Professor Ross Hannon at the Peter MacCallum Cancer Centre, also contributed to the work, which was published in the journal PLOS Genetics this month.
Associate Professor Heath, a Ludwig Institute Member who recently transferred her research group to the Walter and Eliza Hall Institute, said the discovery was made while studying zebrafish embryos that harbour genetic mutations which prevent rapid cell growth during organ development. “Zebrafish embryos provide us with a great laboratory model for these studies because they are transparent, an attribute that allows us to track the growth of rapidly developing organs in live animals under a simple microscope. Moreover, the genes controlling growth and proliferation of developing tissues are essentially identical in zebrafish and humans, and are known to be frequently commandeered by cancer cells.”
“We discovered that a mutation in a relatively under-studied gene called pwp2h leads to the faulty assembly of ribosomes, the ‘protein factories’ of cells, and stops cells from dividing,” she said. “What was intriguing was that cells under stress from ribosome failure did not die. Instead, the cells switched on a survival mechanism called autophagy and began obtaining nutrients by digesting their own intracellular components.”
Ribosomes are large molecular machines in cells that manufacture proteins, and are critical for cell growth and division. Currently, there is great interest in developing therapeutics to block ribosome production, as a strategy to prevent cancer cells from dividing.
“Our research could have implications for this type of cancer treatment,” Associate Professor Heath said. “We showed that when ribosome assembly is disrupted, cells stop growing as desired, but to our surprise they enter a survival state. An anti-cancer treatment that inadvertently promotes the survival of cancer cells through autophagy is clearly not desirable. However, our findings in zebrafish show that if ribosome assembly is blocked and, at the same time, autophagy is inhibited, cells die rapidly. It is possible that a combination of inhibitors that block ribosome function and autophagy could provide an effective anti-cancer treatment,” she said.
Associate Professor Heath’s group is continuing its research at the Walter and Eliza Hall Institute, examining other genetic mutations in zebrafish that disrupt cell growth and division. “We are keen to enhance our approach by applying existing research technologies at the institute,” she said. “We have identified a number of cellular processes that rapidly dividing cells – including cancer cells – depend on, and the next stage is to test whether they could provide new targets for anti-cancer therapy.”
The research was supported by the Australian National Health and Medical Research Council and the Victorian Government.
About the Ludwig Institute for Cancer Research
The Ludwig Institute is an international non-profit organization committed to improving the understanding and control of cancer through integrated laboratory and clinical discovery. Leveraging its worldwide network of investigators and the ability to sponsor and conduct its own clinical trials, the Institute is actively engaged in translating its discoveries into applications for patient benefit. Since its establishment in 1971, the Institute has expended more than $1.5 billion on cancer research.
About the Walter and Eliza Hall Institute
The Walter and Eliza Hall Institute is Australia’s oldest medical research institute, founded in 1915. It is home to more than 700 researchers who are working towards improving the prevention, diagnosis and treatment of diseases including cancer, chronic inflammatory conditions and infectious diseases.