About the Project
The epithelium that lines the urinary bladder (urothelium) both forms one of the tightest barriers in the body and displays a remarkable capacity for repair, indicating a critical balance between differentiation and regeneration. Normal human urothelial (NHU) cells can be maintained in cell culture in differentiated or non-differentiated states [1]. Proliferation in non-differentiated NHU cells is regulated through autocrine activation of the epidermal growth factor receptor [2]; a pathway that is also used by poorly-differentiated basal-like urothelial cancers [3]. By contrast, differentiated NHU cells use alternative growth-regulating signal transduction pathways [4] that may be relevant to understanding the more differentiated sub-type of “luminal” cancers. Our hypothesis that the growth regulatory pathways active in differentiated NHU cells offer alternative pathways for urothelial cancer development will form the aim of this project. Understanding the different pathways driving urothelial tumorigenesis will help in the stratification of patients to offer more targeted therapies.
Funding Notes
This studentship is fully funded by York Against Cancer and covers: (i) a tax-free stipend at the standard Research Council rate (£14,296 for 2016-2017 but typically increases annually in line with inflation) and (ii) tuition fees at the UK/EU rate. The studentship is available to UK and EU students.
References
1. Varley CL, Bacon EJ, Holder JC, Southgate J. FOXA1 and IRF-1 intermediary transcriptional regulators of PPARgamma-induced urothelial cytodifferentiation. Cell Death Differ. 2009;16:103-14. PMID: 18688264.
2. Varley C, Hill G, Pellegrin S, Shaw NJ, Selby PJ, Trejdosiewicz LK, Southgate J. Autocrine regulation of human urothelial cell proliferation and migration during regenerative responses in vitro. Exp Cell Res. 2005;306:216-29. PMID: 15878346.
3. Rebouissou S, Bernard-Pierrot I, de Reynies A, Lepage ML, Krucker C, Chapeaublanc E, Herault A, Kamoun A, Caillault A, Letouze E, Elarouci N, Neuzillet Y, Denoux Y, Molinie V, Vordos D, Laplanche A, Maille P, Soyeux P, Ofualuka K, Reyal F, Biton A, Sibony M, Paoletti X, Southgate J, Benhamou S, Lebret T, Allory Y, Radvanyi F. EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype. Sci Transl Med. 2014;6:244ra91. PMID: 25009231.
4. Fleming JM, Shabir S, Varley CL, Kirkwood LA, White A, Holder J, Trejdosiewicz LK, Southgate J. Differentiation-associated reprogramming of the transforming growth factor beta receptor pathway establishes the circuitry for epithelial autocrine/paracrine repair. PLoS One. 2012;7:e51404. PMID: 23284691.
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