Differential Regulation of mRNA isoform Expression in Metastatic Cancer

Metastasis is the principle cause of mortality in patients with cancer. An increased understanding of the molecular drivers that lead to primary, localised cancer becoming metastatic disease could provide new opportunities for therapy.

An important mechanism of gene function is the posttranscriptional modification of mRNA to generate splice variants that generate gene products with alternative functions. Using gene expression data from several human cancers, the group of Dr English has identified differences in mRNA isoform expression that occurs between localised, early stage disease and metastases that are associated with reduced survival.

This PhD project will investigate these differences in more detail to understand underlying regulatory mechanisms that could be exploited for therapy.

Solid tumours are not only made of the genetically transformed cancer cells but also a large number and variety of recruited stromal cells that are needed to drive cancer growth and metastasis. At the moment it is not clear which cells within the tumours are responsible for the differences in isoform expression associated with metastasis and decreased survival. The PhD student will use a combination of bioinformatics analysis of clinical data sets and experimental models of metastasis to determine if the changes in mRNA isoform expression are derived from the cancer cell population, cells in the tumour stroma or a combination of both.

This information will be used to identify the molecular mechanisms responsible for the switch in isoform expression and show that changing isoform expression from ‘bad’ to ‘good’ could provide a new mechanism for treating metastatic disease.