Dr Elaine Dunlop
'Working towards tailored therapies for inherited diseases and cancer'
My research centres on the inherited conditions, Tuberous Sclerosis Complex (TSC) and Birt-Hogg-Dubé (BHD) syndrome where patients are predisposed to develop cysts and tumours. I aim to understand what is malfunctioning in these cells at a molecular level, with the goal of identifying weaknesses which could be specifically targeted by therapies. As there is crossover between the altered growth pathways observed in these genetic diseases and the pathways which are at fault in sporadic cancer, these future treatments could also be effective for the wider cancer community. Therefore, through a better understanding of disease processes we can work towards stratifying patients based on the genetics of their disease and treating them with appropriately tailored therapies.
Education and Qualifications
2006 PhD (Centre for Cancer Research and Cell Biology) Queen’s University, Belfast
2003 BSc (Hons) Biochemistry, First Class, Queen’s University, Belfast
Awarded Tim Bramley Prize (Top Biochemistry student, 2003) & John Sinclair Porter Scholarship (2001)
Jul 2015 - present Research Fellow, Division of Cancer & Genetics, Cardiff University
Mar 2013 – Jul 2015 Research Associate, Institute of Cancer & Genetics, Cardiff University
Jan 2011 – Feb 2013 Myrovlytis Trust Research Fellow, Institute of Cancer & Genetics, Cardiff University
May 2007 – Dec 2010 Research Associate, Institute of Medical Genetics, Cardiff University
Oct 2006 – Apr 2007 Special Research Scholar, Haematology Research, Queen’s University, Belfast
2016 Welsh Crucible Participant
2016 Member of the European Association for Cancer Research
2014 - present Associate Fellow of the Higher Education Academy
Committees and reviewing
School of Medicine representative on the Cardiff University Research Staff Association
I contribute to teaching modules including:
- ME3024 - Practical Molecular Genetics module (for intercalated students)
- ME3036 - Molecular Genetics and Cell Biology module (for BSc students)
- Year 1 Medicine - Student Selected Component, Literature Review (medical students)
I am a STEM Ambassador, contributing to outreach activities involving school children and patient groups. These include the School of Medicine 'Science in Health Live' event and the Life Sciences Challenge.
My research focuses on the signalling pathways underlying genetic diseases and cancer. Much of my work is concentrated on the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway which controls cell growth, and is disrupted in a number of genetic tumour-disposition syndromes, such as tuberous sclerosis complex (TSC) and Birt-Hogg-Dubé (BHD) Syndrome, as well as in sporadic cancer. More recently I have expanded my research to examine the process of autophagy in genetic disease.
The overall aim of my research is to gain sufficient understanding of the defects underlying TSC and BHD to identify pathways that could be targeted to bring therapeutic benefit to patients. Due to the crossover between the altered signalling pathways seen in TSC, BHD and cancer, these future treatments could also have a benefit for the treatment of sporadic cancer.
The genetic condition, TSC, is caused by mutations in either TSC1 or TSC2, resulting in hyperactive mTORC1 signalling and the development of cysts and benign tumours in the kidneys, brain and other organs. My research into TSC has led to a greater understanding of signalling mechanisms centred on mTORC1. Through this work we not only uncovered how mutations within components of mTORC1 affect the function of the complex, but we also elucidated a novel negative feedback mechanism whereby activation of autophagy and the kinase,ULK1, leads to phosphorylation of Raptor and inhibition mTORC1 (Dunlop et al., 2011). This is important as it represents one means of how the cell turns off cell growth pathways in times of nutrient deficiency. As part of a collaborative team, we also uncovered the molecular signalling defects resulting from certain mutations within the TSC2 gene. This helps our understanding of how these mutations lead to symptoms in TSC patients. I have been involved in collaborations with two groups of United States based researchers, resulting in further discoveries about Raptor phosphorylation (Soliman et al., 2010) and TSC signalling at the peroxisome (Zhang et al., Nat Cell Biol, 2013). Currently, we are investigating how we can exploit the vulnerabilities of cells with hyperactive mTORC1 signalling in order to selectively target them with drug therapies.
My research also encompasses work on the poorly characterised tumour suppressor protein, folliculin (FLCN) which is mutated in BHD Syndrome. This rare genetic condition can cause skin lesions, lung cysts and kidney cancer. I was awarded a two year Myrovlytis Trust Fellowship to investigate mitochondrial changes and HIF regulation in FLCN-deficient cells. In collaboration with a group at McGill University, Montreal, Canada, we revealed that loss of FLCN results in enhanced mitochondrial biogenesis and increased reactive oxygen species (ROS) production. ROS induced HIF transcriptional activity, which could be reversed with antioxidant treatment (Yan et al., 2014). Targeting the altered metabolism of these FLCN-deficient cells may have therapeutic potential.
Additionally, our group uncovered that FLCN plays a role in autophagy, where cells lacking functional FLCN have impaired basal autophagic flux. We discovered that FLCN interacts with two key autophagy components, ULK1 and GABARAP, with ULK1 able to modulate the FLCN-GABARAP interaction (Dunlop et al., 2014). We also confirmed autophagy defects in tumour samples from BHD patients. Our work is continuing to investigate the fundamental cellular role of FLCN.