Inhibition of WNT signalling in colorectal cancer via targeted degradation of FAM83F-CK1a and FAM83G-CK1a complexes.

Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline.

Hyperactivation of WNT/β-catenin signalling is a prominent hallmark of colorectal cancer (CRC). Despite progress in understanding the pathogensis of CRCs, there are still limited treatment options. The Sapkota lab has recently uncovered critical roles for the poorly characterised FAM83 proteins, FAM83F and FAM83G, in activation of WNT/β-catenin signalling. Specifically, FAM83F and FAM83G activate WNT signalling through interaction with CK1α. Furthermore, loss of FAM83G-CK1α interaction and inhibition of WNT signalling underpins the pathogenesis of a skin disorder termed Palmoplantar Keratoderma caused by missense mutations in FAM83G. Excitingly, anti-myeloma drug lenalidomide, which targets the degradation of CK1α also degrades FAM83F and inhibits WNT signalling. This PhD project aims to build on these findings and establish the substrates of FAM83F-CK1α and FAM83G-CK1α complexes in WNT signalling, establish their molecular bases by solving the structures of the complexes, and develop degraders (PROTACs and/or molecular glues) to target the degradation of FAM83F and/or FAM83G to inhibit WNT signalling and proliferation in colorectal cancers. The project will employ a range of cutting-edge technologies, such as CRISPR/Cas9 genome editing, Cryo-EM & crystallography, mass-spectrometry, organoid models, DEL screens to identify tool compounds, and development of optimized compounds into PROTACs. The student will be exposed to working alongside some leading pharmaceutical industries, including Boehringer Ingelheim, Janssen Pharaceuticals, GSK and Amgen, that collaborate with the Sapkota lab. 

The prospective student will be based in the Sapkota lab at the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU within the School of Life Sciences (SLS). The MRC PPU is one of the world’s most renowned centres for research on protein phosphorylation and ubiquitylation (http://www.ppu.mrc.ac.uk/). Many world-leading researchers in the field of signal transduction have trained within the MRC PPU. The major aims of the MRC PPU are to advance understanding of the role of protein phosphorylation and ubiquitylation in cell regulation and human disease, to facilitate the development of drugs to treat diseases caused by abnormalities in phosphorylation and ubiquitylation, to generate reagents and improve technologies. A key remit of the MRC PPU is to train the next generation of scientists who will advance our understanding in this crucial area of medical research. The School of Life Sciences at the University of Dundee, a world-class academic institution with a reputation for the excellence of its research, its high-quality teaching and student experience, and the strong impact of its activities outside academia. With 900 staff from over 60 countries worldwide, the School provides a dynamic, multi-national, collegiate and diverse environment with state-of-the-art laboratory, technology and teaching facilities. 

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.