I am currently Professor of Developmental Signalling within the Division of Molecular and Clinical Cancer Studies within the Faculty of Biology, Medicine and Health, University of Manchester. I am also Associate Dean for Internationalisation (Teaching, Learning and Students).  I have previously been Programme Director for the Developmental Biology degree programme and Deputy Associate Dean for Teaching, Learning and Students within the Faculty of Life Sciences.

My PhD and initial postdoctoral research was undertaken in the laboratory of Alfonso Martinez Arias at the University of Cambridge. Here I investigated the interaction between the Notch and Wnt pathways during Drosophila development. For my second postdoctoral fellowship, I moved to the laboratory of Anthony Brown at the Weill Medical College of Cornell University, New York. My research there focussed on Wnt signalling in mammalian cells including mammary epithelial cells and the developing murine mammary gland.

In 2001, I returned to the University of Manchester to establish my own laboratory and to take up a Wellcome Trust Research Career Development Fellowship. We are currently investigating the role Notch signalling plays in breast cancer. We are particularly interested in how the signalling pathway controls cellular behaviours like proliferation, apoptosis, adhesion and fate and therefore regulates normal mammary gland development, and tumour initiation and progression. We are also investigating the crosstalk between the Notch and Wnt signalling pathways, as mimicking these points of crosstalk may allow the development of novel and very specific drugs to regulate signalling through the two pathways.

Regulation of Cell Behaviour during Mammalian Development

The complex development of multicellular organisms is regulated by surprisingly few signalling pathways that control cellular behaviours as diverse as adhesion, survival, migration, proliferation and fate determination. We are interested in how so many diverse responses can be generated from so few pathways and how developmental signalling pathways regulate cell behaviour.

One way greater diversity can be generated from signalling pathways is through crosstalk. Our detailed genetic analysis in Drosophila has shown that the Notch and Wnt signalling pathways are intimately intertwined. These are two of the most important developmental signalling pathways which are required for multiple aspects of mammalian development and have been linked to several human diseases including cancer. We have shown through the use of reporter gene assays that similar crosstalk occurs in mammalian cells. The molecular details of this are being established currently by examining the physical interaction between pathway components and their localisation. Also the importance of this crosstalk in development is being analysed through the use of in vitro cell models whose differentiation can be regulated by both Notch and Wnt signalling. Finally, through collaboration with other laboratories in the Centre, we are establishing how manipulating these pathways can be used to control pericyte and human mesenchymal stem cell differentiation for tissue engineering.

We are also examining how Notch signalling regulates cell behaviour in the developing mammary gland. We have recently demonstrated that Notch signalling is increased in a wide variety of human breast cancers and that sustained Notch signalling is required to maintain the tumourigenic phenotype of breast cancer cell lines. To understand how this increase in Notch signalling leads to cellular transformation and tumour formation, we have examined its effects on mammary epithelial cell behaviour. Although there is no change in cell fate, we do observe a reduction in cell adhesion leading to a change in morphology, decreased cell proliferation, and increased resistance to anoikis and drug-induced apoptosis. Current experiments seek to unravel the molecular mechanisms that underlie the regulation of these processes by Notch signalling. Also we will relate these changes in cellular properties to the role Notch plays in the development of the gland as a whole. From this we expect to understand how manipulating the Notch pathway affects the morphology of the mammary gland and how this may lead to cancer.