University of Bristol
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The mechanisms driving heterogeneity and stemness during cellular transformation.
Phenotypic plasticity is a major cancer hallmark critical for every stage of tumour progression and is achieved by reversible cellular transitions, and primarily by the epithelial-mesenchymal transition (EMT), and its reversible counterpart MET [PMID:35022204]. Recently, it was shown that cells with hybrid EMT and MET phenotypes (I.e., partial EMT/MET) are the main source of stem cells responsible for therapy resistance, circulatory tumour cells, dormancy, dissemination and recurrence as well as metastasis.
The Wilms’ tumour protein (WT1) is the top immunotherapeutic cancer antigen, because its misexpression is directly linked to therapy resistance, aggressiveness and recurrence in solid and haematopoietic tumours. WT1 maintains the epithelial mesenchymal balance and, our work had showed a direct role in pEMT in embryogenic development [PMID: 21871842]. This is achieved, partly, by WT1’s unique ability to bind both DNA and RNA to regulate gene expression from transcription to translation [PMID 28811308]. However, the molecular mechanisms underlying its role in tumour phenotypic plasticity remain poorly understood. See https://research-information.bris.ac.uk/en/persons/abdelkader-essafi/projects/.
In our recent work, we have confirmed that WT1 is required for this partial EMT during cellular transformation. My lab focus has been on building human cell models of transformation where the oncogenesis is easily induced, while we can also controllably target WT1 degradation and silencing at protein and RNA levels, respectively. This approach allows the differentiation between the role of a myriad of WT1 RNA transcripts and the 36 or so WT1 protein isoforms.
Therefore, the project will dissect these mechanisms using in vitro and in vivo models of cancer progression, sequencing-based approaches as well as gain and loss of function experiments via CRISPR-Cas9 and shRNA. We will also get direct insights into DNA and RNA targets of WT1 and how chromatin accessibility and the 3D genome are reprogrammed upon WT1 loss, misexpression and/or rescue. The project will yield data showing WT1’s function not only during the earliest and most aggressive stages of transformation but also how its role in pEMT impact 3D organoids and in vivo genetic models of cancer. Thus, this project will generate temporal data on WT1 misexpression that may open new preventative and therapeutic avenues.
The student will join a dynamic, international research group situated in the School of Cellular and Molecular Medicine (CMM). Bristol is a Centre for cell and molecular biology with a very vibrant community of cancer biology and embryonic development experts, and the student will benefit from exposure to a wide range of exciting work in this area. The city is exciting, cosmopolitan and culturally diverse, with good flight connections to European cities.
For further information feel free to contact Dr Abdelkader Essafi (Associate Professor of Genetics) at [email protected]
How to apply
Before applying, please read carefully the information on the prospectus Cellular and Molecular Medicine nearmejobs.eu Study at Bristol nearmejobs.eu University of Bristol and make sure you have all the documents listed in the Entry Requirements – Admissions Statement and English Language Requirements.
To apply, follow the link Start your application nearmejobs.eu Study at Bristol nearmejobs.eu University of Bristol and select the programme “Cellular and Molecular Medicine (PhD)”.
If you have questions about the project, please contact Dr Abdelkader Essafi (Associate Professor of Genetics) at [email protected]
If you require assistance with your application, please email [email protected]
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