Understanding the role of Cadherin-17 (CDH17) in prostate cancer metabolism and progression

Website University of Leicester

Last Day to Apply: 31 July 2024

Project description:
Unlike normal tissue, most cancer types increase their uptake of glucose and production of lactate through aerobic glycolysis to generate energy for their survival and proliferation. This metabolic adaptation, or reprogrammed cellular metabolism, is known as the Warburg effect and has long been regarded as one of the hallmarks of cancer [1, 2]. Targeting molecules, enzymes, and regulatory factors associated with the aerobic glycolysis pathway in cancer cells provides promising diagnostic, prevention, and treatment strategies.

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer death in men in the UK, causing around 12,000 mortalities every year, which is about 33 daily. Therefore, identifying innovative and effective targets for preventing and treating PCa is of great clinical need. In our previous studies, we have tried to answer this urgent need by targeting the key glycolytic metalloenzyme enolase, which participates in the penultimate step of glycolysis for synthesizing pyruvate by catalysing the conversion of 2-phosphoglycerate into phosphoenolpyruvate [3]. One of the isoenzymes, γ-Enolase (Enolase 2, ENO2), was shown to functionally contribute to PCa initiation and progression in in vitro, in vivo, and retrospective clinical studies. Importantly, bioinformatic analysis of ENO2 knockout PCa cells demonstrated that a newly discovered member of the cadherin superfamily, Cadherin-17 (CDH17), could be the pivotal element linking glycolysis and PCa aggression.

CDH17 plays a crucial role in cell adhesion and has been shown to be overexpressed in various cancers, such as gastric and colorectal cancer. Evidence suggests that CDH17 may be involved in cancer development via the Wnt signalling pathway and could be enhanced by the Ras/Raf/MEK/ERK signalling pathway [4, 5]. Several CDH17-based clinical agents, including bispecific antibodies, monoclonal antibodies, and CAR-T cells, are currently under development, but mainly for gastrointestinal cancers. However, the precise biological function and mechanism of CDH17 in PCa have not been elucidated. Therefore, this PhD studentship aims to answer this question with a combination of wet and dry lab research approaches and to test the hypothesis that the overexpression of CDH17 contributes to the proliferation and peripheral infiltration of PCa cells.

Research Plan:
To test the above hypothesis, four interconnected objectives will be addressed using human and murine PCa cell lines as models in vitro and in vivo, and using in silico data-centric approaches.

Objective 1: Comprehensively understand the association of CDH17 with PCa using a panel of PCa cell lines, publicly available datasets and cutting-edge statistical genetics methodologies.

Objective 2: Genetically knock out/knock in CDH17 in PCa cells using CRISPR/Cas9 technology.

Objective 3: Determine the CDH17 manipulation-induced cellular changes in PCa cells, including cell proliferation, migration/invasion, apoptosis, glycolysis, dormancy, and cell cycling.

Objective 4: Determine whether genetic modulation of CDH17 leads to changes in PCa initiation and metastasis in vivo.

This 3.5-year, cross-disciplinary project will offer students comprehensive training in key in vitro, in vivo, and in silico techniques. The project will be based at the Leicester Cancer Research Centre, University of Leicester. Our centre is internationally recognised for research in precision therapeutics, pre-clinical models for drug discovery, cancer prevention, and liquid biopsy for cancer detection. Leicester offers a unique combination of infrastructure and expertise that is not available elsewhere in the UK.

Supervisors:
1. Dr Ning Wang nw208@le.ac.uk
2. Professor Karen Brown
3. Dr Jing Chen

Entry requirements:
UK Bachelor Degree with at least 2:1 in a relevant subject or overseas equivalent. The University of Leicester English language requirements apply.

Eligibility
UK and International applicants are welcome to apply.

*EU applicants who hold EU settled or EU pre-settled status please provide PGR Admissions with a share code (the one that starts with S) so we can verify your fee status email to pgradmissions@le.ac.uk.

**International students please refer to the funding section.

To apply for this job please visit le.ac.uk.

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