Structural and biochemical characterisation of polarity complexes in development and disease

Every cell in our body has an intrinsic orientation (or polarity) that is controlled by a universal set of genes known as polarity genes. Loss of this orientation is a defining early feature in cancers, and has been linked to cancer spread or metastasis. Our team has previously identified the gene Scribble as a new human polarity gene that controls cell orientation and whose deregulation increases the risk of cancer by disorganizing the tissue and by increasing the speed at which cells grow within the tissue. In addition, mutation in Scribble and associated genes can lead to life-threatening birth abnormalities such as spina bifida.

This project will establish how Scribble and its biochemical partners contribute to developmental defects and tumour formation by clarifying their molecular mechanism of action and thus enable targeting of these proteins for therapeutic purposes. To achieve this, you will biochemically characterize the interactions between Scribble and known and novel biochemical partners using a variety of biochemical, high-resolution imaging techniques and functional assays. Using X-ray crystallography and Cryo-electron microscopy (Cryo-EM), you will show in atomic detail how they perform their function. Gaining deeper insight into the nature of the interactions that allow Scribble and its partners to perform its function will be critical to formulate novel anti-cancer compounds that aim to exploit the loss of polarity in cancer cells. All structural and biochemical information will be validated for their functional relevance in our well established mouse and cellular models, and therefore rapidly translated into biological information directly relevant to human cancer patients and their outcome.

In collaboration with Dr Marc Kvansakul, LIMS

Funding:  NHMRC