Uncovering a UFMylation-Fanconi anaemia axis to overcome chemoresistance in ovarian cancer

Project Outline

Ovarian cancer, and particularly high-grade serous ovarian cancer (HGSOC), is the most lethal gynaecological cancer. Although initial treatments with platinum chemotherapy are often successful, ~80% of patients relapse. At recurrence, drugs such as doxorubicin are commonly used, but resistance develops rapidly, leaving very limited options and contributing to poor long-term survival. Tackling chemoresistance is therefore a critical unmet need. A subgroup of HGSOC tumours with CCNE1 amplification (15-20% of cases), is especially difficult to treat, as these cancers relapse quickly and resist targeted therapies.

Our recent analyses show that these tumours often also overexpress FANCD2, a DNA repair protein of the Fanconi anaemia pathway that can protect cancer cells from chemotherapy damage. We have discovered that UFMylation, the latest identified ubiquitin-like protein-modifying pathway, is essential to stabilise FANCD2 during chemotherapy stress. This opens up the exciting opportunity to both understand and target a novel vulnerability in resistant ovarian cancer.

The student will explore how UFMylation controls DNA repair and chemotherapy survival. The research will use two innovative platform technologies developed uniquely in Manchester: an antibody-independent UFMylome mapping system that identifies UFMylation sites on proteins with unprecedented precision, and an ultra-low ROS APEX2 labelling method that captures fragile protein interactions without detectably damaging DNA. Alongside these cutting-edge approaches, the student will use a Manchester Living Biobank, one of the world’s largest in-depth annotated collections of patient-derived ovarian cancer models, to test UFMylation targeting strategies for resensitising resistant tumours to chemotherapy.

This project will equip the student with advanced skills in molecular biology, proteomics, and translational cancer research while contributing to Manchester’s internationally recognised ovarian cancer programme. By uncovering how UFMylation drives therapy resistance and identifying ways to overcome it, the research has clear potential to inform future treatment strategies and improve outcomes for patients with the hardest-totreat ovarian cancers.

Applications for this project are now open. Please complete your application on The University of Manchester website.