PhD Studentship: The Role of Fusion Proteins in Tumorigenesis

Salivary gland tumours are uncommon but have a varied and complex pattern of histopathological features. The latest WHO classification contains over 40 named neoplasms, many of which show significant morphological diversity resulting in overlapping features and this makes differentiation between tumour types difficult, even for the most experienced diagnostic pathologist. There is, therefore, a constant need to evaluate potential new biomarkers that could prove to be useful diagnostic and prognostic tools.

Recent evidence suggests that a number of salivary gland tumours are associated with the presence of novel fusion proteins. The exact role for these has not been fully elucidated but it is of interest that the salivary gland tumours are histologically similar to some breast tumours, which also have these same fusion proteins. For example, Mammary analogue secretory carcinoma (MASC), a newly identified salivary gland tumor and named due to its strong resemblance to secretory carcinoma of breast, harbours a characteristic balanced chromosomal translocation t(12;15) (p13;q25) resulting in an ETV6-NTRK3 fusion gene. ETV6 is a transcription factor that plays a role in early haematopoiesis and angiogenesis whereas NTRK3 encodes transmembrane surface receptor for neurotrophin-3 (NT-3) that mediates development in the central nervous system. The fusion protein is thought to function by a ligand-independent dimerization of the chimeric protein, leading to oncogenesis by dysregulating NTRK3 signal-transduction pathways but the true mechanism of action remains to be elucidated.

Adenoid cystic carcinomas, of the breast and salivary glands, have been shown to be associated with a further translocation [t(6;9)q22-23p23-24)] which results in a MYB-NFIB fusion protein. Evidence suggests that this disrupts repression of MYB, leads to overexpression of MYB-NFIB transcripts and protein resulting in activation of critical MYB targets including genes associated with apoptosis, cell cycle control and angiogenesis. This could prove to be oncogenic but the mechanism of action requires further investigation.

Aside from these observations suggesting a common molecular pathway for the development of breast and salivary gland tumours the novel functional activity resulting from the fusion proteins could prove to be candidate therapeutic targets.

ETV6-NTRK3 and MYB-NFIB fusion gene constructs will be generated and transfected into normal human salivary gland cells. We have developed a novel method to isolate primary cells from normal salivary glands and to maintain them in culture using chemically defined growth conditions. We have also shown that these cells can be transfected with plasmid DNA. Following transfection we will study the transcriptional consequences of fusion protein over expression using unbiased RNAseq and apoptotic, angiogenic and migration/invasion assays will inform any change of function.

The project will fully elucidate the role of fusion proteins in tumourigenesis, inform the development of novel diagnostic and prognostic tools and provide novel therapeutic targets.

Funding Notes

The Faculty Scholarships for Medicine, Dentistry & Health cover fees and stipend at Home/EU level. Overseas students may apply but will need to fund the fee differential between Home and Overseas rate from another source.