Ewch i’r prif gynnwys
Yr Athro Trevor Dale

Yr Athro Trevor Dale

Professor / Deputy Research Division Leader (Molecular Biosciences)

Ysgol y Biowyddorau

Email:
daletc@cardiff.ac.uk
Telephone:
+44 (0)29 2087 4652
Fax:
+44 (0)29 2087 4116
Location:
Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, Adeilad Syr Martin Evans, Rhodfa'r Amgueddfa, Caerdydd, CF10 3AX

Research overview

The primary focus of research in the group is the regulation of the Wnt signal transduction pathway. Wnts together with other peptide ligands including the FGF, EGF, TGF-β and hedgehog families orchestrate cell-cell interactions throughout development. Much of the specificity of each ligand's function is controlled by intracellular pathways that are activated at the cell surface. Components of the Wnt/β-catenin pathway are frequently mutated in human cancer. This laboratory studies normal and oncogenic Wnt signalling using approaches ranging from biochemistry/structural biology, through cell and organoid based assays to murine models.

Specific projects include:

  1. The biochemistry of Wnt pathway components such as the kinase GSK-3
  2. The identification of novel Wnt regulators through high throughput cDNA, siRNA and drug screening.
  3. The analysis of normal and oncogenic Wnt signalling using murine models and 3D organoid culture systems

Research in the group has led to the recent establishment of a spin out company to commercialise a novel technology for high throughput quantitative protein-interaction assays. (see www.nanotether.co.uk).

Research division

Molecular Biosciences

I did my undergraduate in Biochemistry at Imperial College and then completed a PhD on interferon signal transduction at the Imperial Cancer Research Fund in 1989 (now Cancer Research UK, London Research Centre). During this time I became interested in the role of signalling pathways in development. Following a postdoctoral fellowship at Baylor College of Medicine in Houston, I established a research group at the Institute of Cancer Research in London in 1991.

My group moved to Cardiff in November 2003.

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Screening for Genes and Small Molecules that Modulate Wnt/β-catenin Signalling

The Wnt/β-catenin pathway is activated in a wide range of tumours. Cell-based screening is an efficient way of identifying novel Wnt/β-catenin regulators. We have used high throughput cell based screening to identify novel proteins and small molecules that regulate the pathway. The novel proteins and small molecules are initially used as molecular tools to further characterise the Wnt pathway. This has enabled us to demonstrate that the Wnt pathway behaves like a molecular network. Some of the small molecules are now being developed as candidate therapeutics for colorectal and breast cancer in a major collaboration with Merck Serono.

Organoid Culture

Three dimensional primary culture systems are more relevant for predicting utility of possible therapeutic agents for use in vivo than 2D culture of established cell lines. Developing medium-throughput organoid culture systems to test Wnt pathway inhibitors is an important research direction for the laboratory. Culture of both normal tissue and tumour organoids are being developed.

Human Colon Organoids

Growth of single organoids were imaged over 4 days  and the videos can be accessed via these links: normal colon organoid , colon tumour organoid .

Axin1's Role in Liver Tumour Development

Mutations in genes encoding proteins in the Wnt signalling pathway, including CTNNB1 (β-catenin gene) and the GSK-3 binding protein AXIN1, are found in more than 50% of human hepatocellular carcinomas (HCCs). A murine model was developed to conditionally disrupt the function of the Axin1 and Axin2 genes in the liver. Livers lacking Axin1 showed greater cell proliferation and developed liver tumours that matched the subtype of human liver cancer in which Axin mutations are found. Surprisingly, the changes observed following Axin loss were different from those that are characteristic of Wnt pathway activation suggesting that Axin may repress liver cancer through a novel molecular pathway.

Biochemistry and Structure of Components of the Wnt/β-catenin Signalling Pathway

We are particularly interested in studying how β-catenin turnover is altered following Wnt ligand binding at the cell surface and following oncogenic mutations. Both Wnt ligands and oncogenic changes stabilise β-catenin and activate β-catenin/TCF-dependent transcription. Work is aimed at understanding how these changes alter the composition and interactions between β-catenin turnover complex components such as APC, Axin and CK1.

High throughput screening for protein interactions

The slowest step in many biochemical assays is the production and purification of  sufficient protein for quantitative assays. In collaboration with Professors Adrian Harwood and Paola Borri, we have developed a novel technique termed 'Nanotether' that could break this biochemical bottleneck.

The idea of behind the technology is to tether two biomolecules to the ends of flexible (DNA) tethers such that they can interact in a nano-scale volume. Arrayed spots of interacting molecules containing as few as 1 million molecules are analysed by FRET to measure the proportion of tethered biomolecules.

The key advantages of the technology are:

  1. Tethered arrays of molecule pairs are easily assembled by DNA hybridisation.
  2. Hybridisation concentrates the interacting molecules near the surface while the length of the tethers control the effective concentration (low nM-uM range).
  3. High concentrations (> 10uM) can be generated from low masses of protein  - this should be compatible with techniques such as in vitro translation.

This technology is now being commercially developed in a Cardiff University spin-out company. The first application area will be high throughput protein kinase binding assays. See www.nanotether.co.uk (Proof of concept data can be found in Perrins et al. 2011.)

Wnt/β-catenin  Signalling and Mammary Development and Tumourigenesis

The mammary gland undergoes numerous developmental processes postnatally, from the elongation of the ductal tree-like structure to the pregnancy-induced development of the lobulo-alveolar units that make milk. Mammary epithelial stem cells have been suggested to be central to the control of enormous tissue expansion and remodelling during these phases of mammary development. The Wnt signalling pathway plays a critical role in these biological steps and is suggested to be involved in the maintenance of the stem cell population. It has also been implicated in certain types of breast cancer.