Research

Overview

The body is constantly making new cells. If they are healthy and regulated properly, these cells replace old dead cells so the body can grow and repair organs that have been damaged. However, if this is uncontrolled too many cells could be made, leading to tumour formation.

In recent years a group of related proteins known as the ‘Hippo Pathway’ has been identified as a regulator of this cell proliferation. Hippo pathway proteins such as YAP and TAZ respond to diverse changes in the cell’s environment with alterations in the rate of cell proliferation, activation of the immune system, and generation of new cell types, amongst others.

An infographic showing cells with low YAP/TAZ activity undergoing normal cell proliferation to replace unhealthy cells, and cells with high YAP/TAZ activity undergoing uncontrolled cell proliferation to form tumours.

How these proteins are regulated and how they perform their functions is the subject of our research, with our focus ranging from molecular to whole body processes. This includes the study of cancer, regeneration, and inflammation using imaging of cells grown in the lab and zebrafish, genetic editing, biochemistry, and gene expression analyses. This all helps towards our eventual aim of identifying targets for more effective cancer treatments with fewer side effects.

scientific Background

Cellular proliferation and differentiation must be tightly regulated to maintain tissue mass and homeostasis. If this regulation is lost cellular overgrowth and cancer occurs. However, proliferation and differentiation need to be under dynamic control for developmental and regenerative process. In recent years the Hippo pathway has been elucidated as a potent regulator in these processes, where it functions as a nexus and signal integrator of diverse cellular signals. The core components of the Hippo pathway comprise a regulatory serine–threonine kinase module and a transcriptional module. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the major downstream effectors in this transcriptional module where they shuttle to the nucleus. There, they predominantly bind to, and regulate the activity of, the TEAD family of transcription factors. These transcription factors promote the expression of a range of genes, including those involved in stem cell proliferation and differentiation, immune system activation, and the extracellular matrix.

An infographic showing cells with high YAP/TAZ activity have roles in immune system activation and infiltration, extracellular niche development and regulation, dedifferentiation and stem cell activation and regenerationt, and tumour formation, leading to cancer metastasis and drug resistance. Medicines are shown to inhibit tumour formation.

Recently, the understanding of the regulatory mechanisms of the Hippo pathway has become a major focus, especially in cancer biology and regenerative medicine. A wealth of cellular regulators has been identified, but how the dynamic subcellular regulation of the core players occurs is not well understood and we seek to answer this fundamental process. We also seek to understand the role of the Hippo pathway in biological processes important for human health with a focus on regeneration, inflammation and cancer.

We are a collaborative and interdisciplinary lab, that utilises live imaging in both mammalian cell culture and the zebrafish in combination with genome editing, biochemistry, label-free holographic imaging and gene expression analyses to address these questions.

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