PhD Studenship: Do cancers recapitulate embryonic processes? If so, how?
The processes driving embryonic development are fundamentally different from those observed in healthy adult cells. That is why most master regulators of cell fate determination and tissue remodeling in the embryo are silenced in the adult. However, in cancer, we observe an abnormal reactivation of some of these master regulators at different stages during disease progression.
Remarkably the early, rather than the late recapitulation of the epithelial-to-mesenchymal transition (EMT), is sufficient to generate migratory and/or chemo-resistant cancer stem-like cells (CSCs). EMT and the reverse process mesenchymal-to-epithelial transition (MET) are major tissue remodeling processes critical for the development of many embryonic tissues such as the kidney and the vasculature. The multifunctional Wilms’ tumour protein (WT1) is a major regulator of the EMT-MET balance in those same tissues. In this project, we are interested in understanding the molecular mechanisms underlying WT1 function as an EMT-MET regulator upon abnormal re-activation in cancers.
Therefore, the candidate will build on our previous findings to a) delineate and b) functionally characterize the molecular mechanisms downstream of WT1 in epithelial cancer. Promisingly, WT1-based immunotherapy clinical trials are underway as WT1 has topped a National Cancer Institute (NCI) antigen prioritization list. This is because as a developmental master regulator, WT1’s well-documented expression in adult tissues is restricted to few non-epithelial cell types yet it is abnormally reactivated uniquely in epithelial cancer cells. Here, we will use a well-established inducible oncogene-transformed epithelial cell model in order to a) investigate the role of Wt1’s multiple isoforms in driving cell fate. To this end we will use sequencing and proteomics-based approaches. Then, we will b) validate a selected and prioritized list of key WT1 targets. To achieve the latter, we will focus on gain and loss of function experiments of those prioritized targets using CRISPR-based tools in in vitro 3D cell culture as well as in vivo models.
Because the abnormal reactivation of the embryonic isoforms of WT1 will hijack embryonic cellular remodelling processes that may directly contribute to cancer aggressiveness; the investigation of mechanisms that are activated upon WT1 misexpression could have major implications for cancer therapy.
Upper-second (2.1) class degree or equivalent in a relevant discipline (Cellular or Molecular Biology, Immunology, Biochemistry). Prior interest or research experience in cell culture and molecular biology techniques will be advantageous.
How to apply:
Please make an online application for this project at http://www.bris.ac.uk/pg-howtoapply. Please select Cellular and Molecular Medicine on the Programme Choice page and enter details of the studentship when prompted in the Funding and Research Details sections of the form.
This is a 3 year funded PhD studentship; funding includes a standard stipend. Funds are also available for tuition fees at 'home' (UK/EEA) rates. Note that UK/EEA Residency legal requirements apply.
1. Essafi A, et al., A wt1-controlled chromatin switching mechanism underpins tissue-specific wnt4 activation and repression. Developmental Cell. (2011) Sep 13;21(3):559
2. Essafi A, Hastie ND. WT1 the oncogene: a tale of death and HtrA. Molecular Cell. (2010) Jan 29;37(2):153-5. Preview
3. Martínez-Estrada OM, et al, Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin. Nature Genetics. (2010) Jan;42(1):89-93
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