Professor Maureen O’Sullivan

Research Description:

The O’Sullivan group focuses on paediatric solid tumour genetics, epigenetics and cell biology. With a particular focus on sarcomas and paediatric renal tumours, the group has characterised several novel chromosomal translocations and studied the biological impact these have on cell biology. These include the 14-3-3e::NUTM2 fusion in Clear Cell Sarcoma of Kidney (CCSK) which we characterised and then explored with our in-house generated cell line models, to show an oncogenic effect through dysregulation of MAPK-AKT signalling. We also identified a panel of diagnostically useful immunohistochemical markers for this tumour. As it turns out, 14-3-3e::NUTM2 is the oncogenic driver of a minority of CCSKs however, with the vast bulk of cases resulting from a mutually exclusive internal tandem duplication (ITD) in BCOR gene. Having characterised this ITD in a large cohort of internationally accrued CCSKs, we have accordingly generated a series of cell lines to model this and are finding intriguing effects of the BCOR-ITD on non-canonical Polycomb Repressor Complex 1 (PRC1.1) formation and function, using a variety of techniques including IP-Mass spectrometry, Size-exclusion chromatography and ChIP sequencing. In an effort to resolve the seemingly different oncogenic drivers (14-3-3e::NUTM2 versus BCOR-ITD) in CCSK, we are exploring commonalities in the effects of these genetic driver events. The various ‘omic’ data are also integrated with Methylation profiling of the tumours and cell line models. Our work has increasingly incorporated an exploration of epigenetic dysregulation which is an important feature of cancer, possibly especially paediatric cancer and an exciting one, given potential targetability of these epigenetic changes. This research has benefits in terms of diagnosis, prognosis, biological understanding and novel therapeutic development for these rare cancers, which are all too often neglected despite their aggressive nature.