Profile

Career

1999 -	Director, Jack Birch Unit and Chair of Molecular Carcinogenesis	Department of Biology, University of York
1993 - 1999	Head of ICRF Group 'Biology of Normal and Malignant Epithelial Cells'	Cancer Medicine Research Unit, University of Leeds
1990 - 1999	Research Fellow, then Senior then Principal Research Fellow	Cancer Medicine Research Unit, University of Leeds
1989	PhD	University of Leeds
1983	GI Biol (2:1 Hons)	Biochemistry Institute of Biology
1978 - 1990	Research Officer	Imperial Cancer Research Fund

Research

Overview

Professor Jenny Southgate is Director of the Jack Birch Unit for Molecular Carcinogenesis (JBUMC) and holds a Research Chair funded externally by York Against Cancer. The research of the JBUMC focuses on human epithelial tissues. Our aims are to understand the processes that control proliferation, differentiation and cellular organisation in normal and wounded epithelial tissues and how dysregulation of these processes leads to the development and progression of malignant disease. Most of the work in the Unit focuses on urothelium, the specialised epithelium that lines the urinary tract and gives rise to bladder cancer, although we also have a developing interest in colorectal cancer. A range of cell and tissue culture systems have been developed to study urothelial cells from normal and diseased tissues, and methods have been established using retroviruses to enable gene manipulation, in order to recapitulate the early stages of neoplastic development. The capacity for in vitro-propagated normal human urothelial cells to undergo differentiation and form a functional urinary barrier has led to an interest in reconstructing bladder cells into functional tissues for the purpose of tissue engineering and we are examining a range of natural and synthetic biomaterials as scaffolds for this purpose.

Discoveries

• We have developed methodologies to isolate normal human urothelial cells from urological samples and to establish them as cultures in serum-free medium. • In culture, normal human urothelial (NHU) cells may be maintained as finite cell lines and adopt a regenerative phenotype driven by autocrine epidermal growth factor receptor signalling. • NHU cell cultures do not differentiate spontaneously, but may be induced to form a stratified, differentiated urothelium with functional barrier properties; we have patented this technology (WO/2004/011630). • We have implicated the nuclear receptor, peroxisome proliferator activated receptor gamma (PPARγ) in urothelial differentiation. PPARγ activation in EGFR-inhibited NHU cells results in de novo expression of intermediary transcription factors that mediate a cascade of gene expression changes associated with terminal urothelial cytodifferentiation. • NHU cell cultures are susceptible to genetic modification with retroviruses, providing a means to generate paramalignant sublines that express cancer-modified genes. For example, urothelial cells expressing a dominant negative p53 gene acquire insensitivity to inhibitors of EGFR signalling pathways. This has implications for bladder cancer therapy, as combination treatments with conventional chemotherapy or radiotherapy may protect normal cells and enable better selective targeting of malignant cells. • The process of regenerative repair in normal human urothelial cell sheets is initiated by two independent responses to trauma: a sustained rise in intracellular calcium due to uptake of extracellular calcium in cells adjacent to the wound edge and a transient calcium wave that propagates away from the wound edge and involves inositol-1,4,5-triphosphate (IP3) receptor-mediated release of calcium from intracellular stores and the diffusion of extracellular agonists, including ATP. • Our work indicates that the calcium signature, defined by its temporal and amplitude characteristics, is important in co-ordinating the response of urothelial cells within an epithelial cell monolayer after wounding. • Normal urothelium from abattoir pig bladders has many cell biological properties equivalent to normal human urothelium, including capacity for propagation in culture and ability to reconstitute a differentiated, functional tissue. This makes it a useful surrogate for difficult-to-obtain human bladder tissue for research. • The ability to propagate and differentiate NHU cells has potential applications in bladder tissue engineering and reconstructive surgery. We have developed an experimental surgical model and in collaboration with other scientists, have developed novel natural and synthetic biomaterials as potential scaffold materials.

Current projects

• The Epitheliome: computational modelling of epithelial tissue ( Funding body: EPSRC)
• Jack Birch Unit of Molecular Carcinogenesis 5 year support (Funding body: York Against Cancer)
• Role of PPARgamma-Regulated Transcription Factors (Funding body: York Against Cancer)
• Role of PPARgamma-Regulated Transcription Factors (Funding body: York Against Cancer)
• The role of wnt signalling in urothelial carcinogenesis  (Funding body: York Against Cancer (Lisa Clements PhD studentship))
• Matrix remodelling and cellularisation of biomaterials for tissue engineering (Funding body: BBSRC Industrial Case Studentship with Tissue Regenix (S Bullers))
• The role of PPARs as signalling molecules in colorectal cancer (Funding body: York Against Cancer)
• The Biomimetic Urothelium (Funding body: BBSRC/RSE)

Research group(s)

Status	Name	Project
Administrative	Marie Fleming	0.95 FTE
Clinical research fellow	Graeme Macaulay (writing up)	The Role of PPARs as Signalling Molecules in Colorectal Cancer
Clinical research fellow	Mr Felix Wezel	Identification, propagation and differentiation of putative stem cells in normal human urothelial cells in vitro
Clinical research fellow	Dr Khurram Shahzad	Ketamine-induced bladder dysfunction
Post doctoral researcher	Dr Claire Varley
Post doctoral researcher	Dr Simon Baker	The Urotheliome
Post doctoral researcher	Dr Zac Shabir	A combined in vitro and in virtuo multi-scale approach to understanding calcium signalling as a signature and integrator of cellular response
Rsearch student	Lisa Kirkwood (writing up)	The role of wnt signalling in urothelial carcinogenesis
Rsearch student	Jenny Hinley (part-time MPhil)
Research Student	Sam Bullers	Matrix Remodelling and Cellularisation of Biomaterials for Tissue Engineering
Research Student	Carl Fishwick	Epigenetic regulation of proliferation and differentiation in human bladder epithelial cells.
Technician	Lisa Kirkwood	0.2 FTE
Technician	Jenny Hinley	1 FTE
Technician	Catherine Thompson	0.68 FTE
Technician	Ruth Morton	0.27 FTE
Technician	Ros Duke	0.73 FTE

Available PhD research projects

Homeostatic mechanisms in human urothelium: balancing tissueregeneration and differentiation (for 2012-13)

The urothelium is the self-regenerating epithelium that lines thebladder, where it is highly specialised to function as a urinarybarrier.  Although normally a mitotically-quiescent tissue, urotheliumshows a rapid and highly regenerative response to damage.  Whether thereis a specific progenitor or stem cell population remains controversial,as no such cell has been unequivocally identified. An alternativehypothesis is that all cells remain capable of switching into aregenerative phenotype, irrespective of differentiation state.  Theproject will examine this hypothesis in a well-established cell culturesystem, using a combination of cell and molecular biology approaches toexamine the role of cell:cell interactions, downstream signaltransduction and epigenetic regulation.

Publications

Selected publications

Baker SC and Southgate J (2008) Towards control of smooth muscle cell differentiation in synthetic 3D scaffolds Biomaterials 29: 3357-3366

MacLaine NJ, Wood MD, Holder JC, Rees RW and Southgate J (2008) Sensitivity of normal, paramalignant, and malignant human urothelial cells to inhibitors of the epidermal growth factor receptor signaling pathway Mol Cancer Res 6: 53-63

External activities

Memberships

• Member: EPSRC peer review college
• Chair: University of York Ethics Committee
• Chair: Yorkshire Biomaterials and Tissue Engineering Group
• Member: BBSRC Committee C