Research Projects
Main Research Topics of the Epithelial Cancers Laboratory:
A paradigm that has emerged over several decades from diverse fields of cancer research is that uncontrolled cellular proliferation and tumour initiation in most epithelial cell types results not from the mutation of single genes, but rather involves the dysregulation of multiple tumour suppressor and/or oncogenic pathways that act in a cooperative manner to induce proliferation. Major current themes of our research centre around unraveling the potential cooperative roles of oxygen-regulated signaling pathways (VHL tumour suppressor protein and HIFα transcription factors), cell cycle regulatory networks, Wnt- β-catenin signaling and signaling by the primary cilium in kidney and endometrial tumours.
We employ four mutually complementary approaches to identify and characterise the cooperating signaling networks that regulate kidney and endometrial epithelial cell proliferative homeostasis:
i) Mouse genetics. We utilise conditional gene knockout approaches to delete cancer-relevant genes specifically in the epithelia of the kidney and endometrium, with the aim of generating novel mouse models of human tumours.
ii) Mouse genetics – technology development. We are developing a novel in vivo experimental system that will allow the analysis of gene function in control of proliferative homeostasis in the mouse in a high-throughput and systematic manner. This system is based upon lentiviral-mediated simultaneous up- and/or down-regulation of gene expression and the use of live animal imaging to identify and track tumour formation and development. We envisage that this technique will be widely applicable to multiple organ systems in the mouse and will represent a powerful experimental platform that will allow the in vivo manipulation of gene expression of individual genes or of multiple genes simultaneously, bypassing the time limitations imposed by classical transgenic and knockout approaches.
Collectively these mouse genetics-based studies aim to provide insight into the molecular mechanisms that control kidney epithelial cell proliferation in vivo and ultimately to provide mouse models for testing novel therapeutic approaches for these currently untreatable diseases.
iii) Mouse primary cell culture-based assays. We utilise hypothesis-driven, as well as genetic screening-based, experimental approaches using primary cells derived from genetically modified mice to characterise the oncogenic and tumour suppressor pathways that act to either promote or restrain proliferation of epithelial cells. These studies aim to understand the process of cancer development through a “cancer building” approach, i.e. by asking what genetic changes are necessary to turn primary cells into cancer cells. Additionally they serve to identify and validate particular gene products and signaling pathways as potential targets for therapeutic intervention in tumours that harbour specific combinations of genetic mutations.
iv) Translation of research findings to human disease. An ongoing goal of our research is to utilise knowledge gained in functional genetic studies to identify the genes that are important in human diseases and, in turn, to utilise studies of human tumours to guide molecular mechanism-based studies in the lab. The relevance of findings derived from mouse-based functional studies to human pathology is tested through collaborative studies with tumour pathologists to analyse the genetic and signaling alterations that occur in human tumours. We also employ cell culture-based assays using primary and transformed human cells to test the functional importance in humans of genes that arise from our mouse-based laboratory studies.