Hippo-YAP/TAZ signalling in stem cells, regeneration and cancer
Most human cancers arise in epithelial tissues, such as the skin or intestinal tract. A population of basal stem cells normally proliferates to maintain epithelial homeostasis and to regenerate tissues after damage. The same stem cells are also the origin of tumour formation. We seek to understand how epithelial stem cells normally function and how their activity becomes mis-regulated in cancers.
My laboratory uses Drosophila, mouse and human organoids in culture as model systems to explore how stem cells construct epithelial tissues during development and how epithelial tumours can arise.
We focus on the questions of how cell polarity organises the behaviour of cells within an epithelium, and how signalling pathways control cell proliferation within an epithelia. A major interest has been the Hippo-YAP/TAZ signalling pathway, which responds to apical and basal polarity cues, cell-matrix interactions, and mechanical forces to regulate cell proliferation and cellular morphology during development.
Our experiments combine three main approaches to identify molecular mechanisms responsible for organising cell polarity and cell behaviour during tissue growth and morphogenesis in epithelia:
- Genetic analysis of gene functions in vivo;
- Live-imaging of epithelial tissue development; and
- Organoids and tumour cells in culture
- Mouse models of tumour growth and metastasis
- Analysis of human cancer patient samples
- Genetic analysis of gene functions in vivo;
- Live-imaging of epithelial tissue development; and
- Computational modelling of cell polarity and cell behaviour.
- Mechanisms of signal transduction via the Hippo-YAP/TAZ pathway
- Regulation of Hippo-YAP/TAZ by epithelial polarity, cell adhesion, extracellular matrix and tissue damage
- Role of YAP/TAZ in tissue development, stem cells and regeneration
· YAP/TAZ as a driver of squamous cell carcinoma progression to metastasis
· YAP/TAZ as a driver of colorectal cancer progression to metastasis
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Mechanical strain regulates the Hippo pathway in Drosophila. Development (2018) 145(5). |
Mechanical strain regulates the Hippo pathway in Drosophila. |
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PLOS Biology (2019) Oct 15. |
The Hippo pathway integrates PI3K-Akt signals with mechanical and polarity cues to control tissue growth. |
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Integrin signalling regulates YAP and TAZ to control skin homeostasis. Development (2016) 143: 1674-1687. |
Integrin signalling regulates YAP and TAZ to control skin homeostasis. |
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The Spectrin cytoskeleton regulates the Hippo signalling pathway. The EMBO Journal (2015) 34: 940-954. |
The Spectrin cytoskeleton regulates the Hippo signalling pathway. |
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Cell (2006) 126(4): 767-74. |
The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. |