The human Fallopian tube is an organ of prime importance to human reproduction and fertility. Despite this, our understanding of general Fallopian tube biology is nascent and lagging in comparison to other organs such as the intestines, skin, breast and others. My DPhil project focuses on a fundamental question: how does the Fallopian tube regenerate? In other words, I seek to identify and characterize the stem cells of the Fallopian tube, which surprisingly have not been identified to date.
Traditionally, researchers grow patient or animal-derived cells in 2D culture on plastic dishes, using minimal growth medium. Such culture conditions are not only poorly reflective of in vivo conditions, but also exhaust stem and other cell types present in live organs, precluding studies on them. A recently pioneered advanced culture technology is able to preserve cell type diversity in vitro. Termed organotypic or organoid cultures, this biotechnology relies on culturing patient or animal-derived cells in 3D ECM scaffolds and maintaining the culture using advanced culture medium containing recombinant proteins that selectively stimulate stem cells to self-renew and differentiate. The result is the re-creation of the organ in the lab, from its resident stem cells, to give rise to self-organizing and self-renewing ‘mini-organs’. Organoid cultures are more reflective of in vivo organs compared to traditional 2D cultures, because they form spatially in 3D, require no genetic manipulation for immortalization, are supported by an extracellular matrix and contain all the cell types present in the organ from which they were isolated.
During my DPhil project, I optimized protocols for long-term expansion of FT organoids from mouse and patient-derived human samples. Subsequently, I was able to show that a small percentage of cells within these organoids are multipotent, possessing the potency to give rise to all other cell types. I identified key signaling pathways important for organoid formation by these multipotent cells, and I hypothesize that these cells are the stem cells of the Fallopian tube. To investigate this further, I was successful in genetically engineering an organoid line containing a stably-integrated fluorescent reporter of these cells. Currently, my research focus is to isolate these cells and test whether multipotency and organoid formation is restricted to them. Eventually, I will isolate these cells for deep transcriptomic analyses, to understand what makes them different and what gives them a stem cell character.
If successful, this work will have a significant impact in the fields of fertility, regenerative medicine, development and in modelling FT pathologies in the lab. In the field of ovarian cancer, there is strong evidence to suggest that the Fallopian tube is the tissue-of-origin of ovarian cancer. Showing how Fallopian tube stem cells relate to ovarian cancer, or indeed whether they are the cells-of-origin of this type of cancer, will be of significant impact in the future detection and treatment of ovarian cancer.
I did my undergraduate education in Human/Medical Genetics at the University of Leicester, under a scholarship from a US foundation and Leicester University. During this BSc degree, I developed a scientific interest in cancer genetics, particularly in the genetics of tumour initiation. I also undertook a 2-month summer placement funded by the Genetics Society, focusing on mechanisms that mediate the import of nucleus-encoded proteins into organelles, using Arabidopsis thaliana as a model system. My final year thesis focused on developing a fast, cheap and reliable method for quantifying locus-specific CNVs in the human genome.
To pursue my interest further, I undertook a Master's degree at the University of Cambridge, funded by an overseas MPhil Research Award. During this project, I examined the role of certain signaling pathways in establishing the 3D architecture of intestinal epithelia, and how polarity dysregulation can be a key event in tumour initiation. I conducted this using mouse-derived intestinal organoids. My time in Cambridge really inspired my interest in 3D organotypic culture methods and harnessing them to further our understanding of stem cell biology and for cancer disease modelling.
I initially joined the Ovarian Cancer Cell laboratory as a Research Assistant in Oct 2015. For 1 year, I served on an MRC-funded project to pharmacologically validate inhibitors targeting key survival pathways activated by crosstalk between ovarian cancer cells and adipocytes in the tumour microenvironment. In Oct 2016, I started my PhD in the same lab, funded by a Clarendon Scholarship and the NDWRH department. The focus of my PhD is to identify and characterize Fallopian tube stem cells using mouse and human FT organoids (see left for more details).