In Melbourne, researchers are investigating how the "Hippo pathway" functions at a molecular level, providing valuable insights into its potential as a therapy for mesothelioma, a deadly cancer.
The team has captured unprecedented microscopy footage demonstrating the activity of DNA-binding proteins—TEADs and YAP—crucial to the Hippo pathway's operation.
Professor Kieran Harvey notes that this pathway evolved over a billion years ago and functions similarly across various species, from single-celled organisms to humans. It regulates tissue growth, wound healing, cell proliferation and death, as well as being implicated in cancer development.
Two new drugs targeting the Hippo pathway are currently undergoing first-in-human trials at Peter Mac for treating mesothelioma, often caused by asbestos exposure.
"The Hippo pathway governs transcription, interpreting our DNA's instructions, but the process is not well understood," says Professor Harvey, affiliated with both Peter Mac and Monash University.
In this study, they employed cutting-edge microscopy to observe in real-time how these proteins function within human cell nuclei, binding to DNA.
The research revealed that the Hippo pathway controls gene expression by regulating the duration TEADs and YAP bind to DNA. Specifically, TEAD1 is known for its role in mesothelioma development, and drugs inhibiting TEADs are being evaluated for potential therapeutic benefits.
Additionally, the study examined epithelioid hemangioendothelioma, a rare cancer caused by the fusion protein YAP-TFE3. The mutated YAP was found to bind DNA for longer periods than YAP or TEADs.
The research led by Dr. Benjamin Kroeger at Peter Mac and Monash University has significant implications for developing therapies targeting these proteins. Their findings have been published in the journal Science Advances.
Science Advances"Given its fundamental role, enhancing our understanding of the Hippo pathway could open new pathways for treating mesothelioma and other challenging cancers," Professor Harvey says.
The study is titled "Hippo signaling regulates nuclear behavior and DNA binding times of YAP and TEAD to control transcription".