My interests in the biological sciences emerged during a research project in the Ecuadorian rainforest, funded by Harvard University, followed by work in the USA on how genes function in normal and diseased states, using the fruit fly as an in vivo genetic model.  Back in the UK and during my PhD, I used this same model to identify changes in cell growth that were more difficult to detect in other systems:  showing that a recently identified human tumour suppressor gene, PTEN, functions as a brake on the oncogenic PI3-kinase pathway (Genes & Development 1999). 

Having initially studied Chemistry at the University of Oxford and switched to Biochemistry at the University of Kent for my PhD, I focused as a postdoctoral researcher on the regulation of the nutrient and microenvironmental sensor mTORC1, which is a downstream target of PI3-kinase/PTEN signalling and which acts to co-ordinate growth and metabolism.  Collaborative work, with Prof Richard Boyd and Prof Clive Wilson (both DPAG), showed that members of the proton-assisted amino acid transporter family can act as growth promoters, not via transport activity, but via their ability to sense amino acids and then signal to downstream protein targets (Development 2005). 

By 2005, my research group was investigating the role of these transporters in cancer biology and tumour progression.   In 2015, I began leading a Cancer Research UK (CRUK) Programme investigating the links between amino acid sensing, mTORC1 signalling and communication between cells involving small secreted vesicles known as exosomes.  This resulted in the identification and characterisation of Rab11a-exosomes as a potent new exosome subtype.  DPhil students in my group working with our clinical collaborator, Assoc Prof Chris Cunningham (NDS), on patient samples have extended this research, uncovering roles for these exosomes in therapy resistance and their potential for cancer diagnostics.  With support from the BBSRC and CRUK, we identified specific cellular mechanisms controlling Rab11a-exosome formation and function.  Since 2016, I been an Associate Professor of Cell Signalling. 

In addition to undertaking research, since 2015 I have been a member of the Cancer Research UK Oxford Centre Research Committee.  In 2016, I was one of two colleagues involved in re-establishing and rebranding ‘Oxosome: The Oxford Extracellular Vesicle Group’, which promotes interactions between local research groups working in this field.  Since 2020, I have served on the Board of Directors of the International Society for Extracellular Vesicles (ISEV):  most recently, I had a short spell as the Interim Executive Scientific Editor for their journal, namely the Journal of Extracellular Vesicles.  I am currently part of a small committee leading the compilation of the MISEV2023 extracellular vesicle field consensus paper.

RESEARCH

I have transferred my research programme to the Nuffield Department of Women’s and Reproductive Health, where I hope to work with colleagues to uncover new ways of exploiting, in a clinical setting, recent findings from my group.  Our previous studies revealed that exosomes, under the spotlight as major players in cell communication, can be made in a range of sites within cells. 

Exosomes, which are a type of small extracellular vesicle (EV), carry complex mixtures of proteins and other biomolecules and affect the behaviour of target cells in a wide range of tissues, both in health and disease.  A major stumbling block to the clinical application of EVs relates to the heterogenous nature of these secreted vesicles and the technological challenges associated with separating and concentrating them.  This has made it difficult to establish which of these vesicles are the key players in signalling.  My research group has used genetic approaches to address these questions, combining biochemical analysis in human cancer cell lines with visualisation of exosome formation, using a fly model, collaboratively developed with Prof Clive Wilson (DPAG; Journal of Cell Biology 2014; The EMBO Journal 2020, News & Views, The EMBO Journal 2020).

Working with Prof Adrian L Harris (Oncology) and Prof Clive Wilson, initially funded by a CRUK Programme, my group demonstrated that the intracellular origin of exosomes contributes to their heterogeneity.  We showed that exosomes, previously thought only to be made in late endosomes, can also be made in Rab11a-labelled recycling endosomes.  These latter exosomes, which we termed ‘Rab11a-exosomes’, are preferentially induced by cellular stresses (The EMBO Journal 2020).  An important consequence of this finding is that key signalling molecules recycled through this system can be selectively loaded in to Rab11a-exosomes.  Comparative proteomic analysis, in collaboration with Assoc Prof Roman Fisher (Target Discovery Institute) has identified routes to block selectively Rab11a-exosome formation and also functions, for example, the effects of seminal fluid EVs on the behaviour of mated female flies (Journal of Cell Biology 2014; Journal of Extracellular Vesicles 2023).  In fact, these exosomes appear to be particularly potent and perform several key functions of EVs in a range of physiological and pathological contexts, even though they seem to represent only a small fraction of all EVs. 

Complementing this work and continuing the collaboration with Prof Wilson, a BBSRC-funded study identified ways by which Rab11a-exosomes interact with each other and with secreted protein aggregates that can themselves also have a signalling role:  findings with significant implications for bio-delivery (Nature Communications 2021).  In addition, we have shown, in collaboration with Prof Chris Cunningham (NDS), that these exosomes mediate important signals involved in cancer progression.  

Our work suggests that Rab11a-exosomes may also have fundamental roles in signalling by reproductive tissues that, for example, ultimately control the interactions between mother and conceptus.  Indeed, there is already biomarker evidence in the literature suggesting that Rab11a-exosomes and their associated protein aggregates may generate signals in breast milk, and in disorders such as preeclampsia and endometriosis.  It is hoped that investigating the production and roles of Rab11a-exosomes in these different scenarios will lead to a better understanding of exosome signalling in women’s and reproductive health, with improved diagnostic and treatment possibilities.