Role of ubiquitin ligases in Non Small Cell Lung Cancer

This 4 year PhD studentship offered in Professor Angeliki Malliri’s group is based at Alderley Park, Cheshire

Lung cancer is the most commonly diagnosed cancer as well as the most common cause of cancer related deaths worldwide, with non-s
small cell lung cancer (NSCLC) being the major histological subtype. Despite growing knowledge of the molecular mechanisms driving lung cancer formation and progression, and the development of novel therapeutic agents, the overall 5-year survival of patients diagnosed with lung cancer remains less than 15%, indicating an ongoing need for innovation.

E3 ubiquitin ligases are a large family of proteins that catalyse the ubiquitination of many protein substrates, targeting them for degradation by the proteasome. Thereby, E3 ubiquitin ligases regulate a variety of cell processes including proliferation, apoptosis, migration and invasion. E3 ubiquitin ligases are often found overexpressed in human cancers, including lung cancer, and their deregulation has been shown to contribute to cancer development. Moreover, recent successes in the development of potent and specific small molecule inhibitors of E3 ligases have provided proof-of-concept that this is a druggable class of protein.

Previously, the Cell Signalling group lead by Professor A. Malliri at the CRUK Manchester Institute demonstrated the involvement of an E3 ligase in the regulation of lung cancer cell adhesion and motility (Cell Reports 10(1): 88-102, 2015). Recently, the group has identified an E3 ligase which appears essential for NSCLC formation in a widely utilised in vivo model.

The successful PhD student candidate will continue this line of investigation by identifying substrates of the E3 ligase using proteomics and establishing the cellular processes regulated by ligase and substrate(s) and the underlying biochemical mechanism(s). Further, the student will address the role of the E3 ligase and substrate(s) in tumour maintenance in in vivo models, thereby validating these molecules as potential therapeutic targets. This will be further underscored by examining their expression and mutational status within human NSCLC tumour specimens, using histology and mining existing databases.

The student will therefore be trained in a range of current molecular, biochemical and cell biological techniques, working with in vitro and in vivo models, and also database analysis in a vibrant laboratory environment with an extensive and documented track record in graduate student supervision.

Closing date: Monday 3 December 2018 – 17:00 hrs GMT.

Interview date: Monday 14 January 2019, Alderley Park, Cheshire.